Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.

Introduction

Despitemajor advances in targeted therapy, KRAS-mutant NSCLC remained refractory to direct inhibition for more than three decades. The discovery of the switch-II pocket (SII-P) in the GDP-bound form of KRAS G12C finally enabled covalent, allele-selective inhibitors, and regulatory approvals of sotorasib (FDA, May 2021) and adagrasib (FDA, December 2022) translated this biochemical insight into clinical benefit (Ferrer et al. 2018 ; Ebright et al. 2025 ; Skoulidis et al. 2021 ; Jänne et al. 2022 ). However, the field now confronts a more nuanced challenge: median progression-free survival (mPFS) with second-line KRAS G12C inhibitor (G12Ci) monotherapy remains below 6 months in randomised phase 3 trials, and no overall survival (OS) benefit over chemotherapy has been demonstrated for sotorasib in the second-line setting (de Langen et al. 2023 ). This reality has shifted the central clinical questions from ‘Is KRAS G12C druggable?’ to ‘How do we deepen and extend responses, and overcome resistance?’ (Oya et al. 2024 ; Shaverdashvili and Burns 2025 ; Jain et al. 2021 ). With over 2.5 million new cases and about 1.8 million fatalities in 2022, lung cancer was the leading cause of mortality and the second most common cancer among both sexes and all age groups based on the IARC GLOBOCAN database (Bray et al. 2024 ; Singh and Agrawal 2021 ; Sung et al. 2021 ). These epidemiological features establish a large and clinically well-defined patient population for targeted intervention.

The landscape has evolved substantially since 2023. Four KRAS G12C inhibitors now carry regulatory approval across global markets. Phase 3 confirmatory data for both approved Western agents have been reported. A new class of next-generation inhibitors with superior pharmacokinetics, enhanced potency, and early signals of meaningful first-line activity has entered advanced clinical development. The co-mutation landscape (STK11, KEAP1, SMARCA4, CDKN2A) has been established as a clinically actionable biomarker system. The first-line paradigm is being directly tested in multiple registrational trials.

While prior reviews have summarised KRAS G12Ci development, this work focuses on mechanism-stratified drug repurposing framework that links resistance pathways to actionable therapeutic strategies, including (i) integration of recent phase 3 clinical data; (ii) coverage of four regulatory approvals and six next-generation clinical-stage inhibitors updated through early 2026; (iii) a mechanism-stratified drug repurposing framework that directly links established resistance pathways to repurposed compounds; and (iv) positioning of IRE1α/unfolded protein response inhibition as a cross-cutting resistance vulnerability with an emerging clinical rationale. This review maps the current state and future trajectory of KRAS G12C-targeted therapy in NSCLC through examination of molecular biology, resistance mechanisms, the expanding inhibitor portfolio, first-line clinical strategy, drug repurposing approaches, advanced preclinical platforms, and translational challenges.

The biology of KRAS G12C

KRAS G12C arises from a single-nucleotide transversion at codon 12 of the KRAS gene, substituting glycine with cysteine. This substitution impairs the intrinsic GTPase activity of KRAS and reduces the rate of GTP hydrolysis, shifting the equilibrium toward the active, GTP-bound ON state and sustaining oncogenic downstream signalling (Batrash et al. 2023 ; Zhu et al. 2022 ). KRAS G12C is the most common KRAS mutation in NSCLC (14%), followed by G12V, G12D, G12A, G12S, and G12R (El Osta et al. 2019 ). The presence of a reactive cysteine enables covalent targeting of the switch-II pocket (SII-P) in the inactive GDP-bound state. However, the predominance of the active GTP-bound state limits the effectiveness of first-generation inhibitors and has driven the development of RAS(ON) inhibitors (Zhu et al. 2022 ; Filis et al. 2025 ).

Mounting evidence links deregulated mitogen-activated protein kinase (MAPK) signalling to a variety of malignant cancers, including NSCLC (Ferrer et al. 2018 ; Jain et al. 2021 ). Figure 1 depicts the KRAS G12C signalling axis and approved inhibitors. Receptor tyrosine kinases like EGFR undergo dimerisation and autophosphorylation, forming docking sites for GRB2 and SHP2. GRB2 recruits the exchange factor SOS to the membrane, where SOS promotes GDP–GTP exchange on KRAS, activating downstream RAF-MEK-ERK and PI3K-AKT-mTOR signalling. Activated ERK then enters the nucleus to drive transcriptional programmes supporting proliferation and survival. Alterations like BRAF, MEK1, or MET activation, or loss of NF1 or PTEN, further amplify signalling and contribute to therapeutic resistance (Ebright et al. 2025 ; Oya et al. 2024 ; Batrash et al. 2023 ). Additional regulators such as AURKA, KEAP1, NRF2, MYC, and YAP modulate this axis. KRAS G12C inhibitors act by covalently trapping the inactive form or targeting the active form, thereby blocking the signalling process and limiting tumour growth (Oya et al. 2024 ; Zhu et al. 2022 ). These signalling dependencies and adaptive rewiring mechanisms create therapeutic vulnerabilities that can be exploited using rational combination and drug repurposing strategies. Fig. 1 Illustration of the core signalling networks driven by KRAS G12C, including MAPK and PI3K pathways, highlighting key upstream and downstream regulatory nodes involved in tumour progression and resistance. Approved and emerging KRAS G12C inhibitors are mentioned to highlight drug candidates for active and inactive states. Created in BioRender.com

Co-mutation landscape and prognostic significance

The clinical actions of KRAS G12C NSCLC are markedly shaped by co-occurring genomic alterations. The most clinically relevant co-mutations are in TP53 (38% of cases), STK11 (34%), CDKN2A (18%), ATM (16%), and KEAP1/NFE2L2 (16%) (Skoulidis et al. 2025 ). These co-mutations define biologically distinct subgroups with differential therapeutic vulnerabilities.

STK11 (LKB1) co-mutations are present in over one-third of KRAS G12C NSCLC cases and are strongly associated with PD-L1 expression, reduced tumour-infiltrating lymphocytes, and poor responses to immune checkpoint inhibitors (Skoulidis et al. 2025 ). Paradoxically, these patients may derive meaningful benefit from KRAS G12C inhibitors as monotherapy, making the STK11 co-mutation a biomarker for preferential first-line KRAS G12Ci use. However, even among KRAS G12Ci-treated patients, STK11 co-mutation is associated with inferior outcomes: IBI351 (fulzerasib) exhibited an ORR of 35.7% in STK11-mutated tumours vs. 63.5% in STK11 wild-type ( p = 0.026) (Zhou et al. 2024 ). Sotorasib clinical response was significantly worse in STK11-co-mutated tumours in the Skoulidis et al. biomarker analysis (Skoulidis et al. 2025 ).

KEAP1 mutations, which constitutively activate the NRF2 antioxidant programme, co-occur in approximately 16% of KRAS G12C cases and are independently associated with poor outcomes on KRAS G12Ci. The triple co-mutation genotype KRAS G12C/STK11/KEAP1 is found in a significant minority of patients and is associated with particularly poor outcomes, with sotorasib ORR of only 23% in this subgroup (Skoulidis et al. 2025 ; Miyashita et al. 2024 ). SMARCA4 and CDKN2A co-mutations have been identified as independent negative predictors of progression-free and OS with first-generation inhibitors (Shaverdashvili and Burns 2025 ). A landmark biomarker analysis by Skoulidis et al. identified TTF-1 negativity and NRF2 pathway activation as molecular determinants of reduced sotorasib efficacy, providing a mechanistic explanation for resistance in these co-mutated subgroups (Skoulidis et al. 2025 ).

Mechanisms of resistance to KRAS G12C inhibitors

Resistance to KRAS G12C inhibitors arises through on- and off-target mechanisms and is clinically categorised as intrinsic (primary) resistance—present at baseline and responsible for lack of initial response, or acquired (secondary) resistance—emerging under therapeutic pressure. Understanding this distinction is necessary for designing rational combinatorial strategies (Table 1 ) (Akhave et al. 2021 ; Mohanty et al. 2023 ; Riedl et al. 2025 ). Table 1 Summary of key resistance mechanisms to KRAS G12C inhibitors Resistance type Mechanism Representative example Therapeutic implications Intrinsic (on target) Co-mutations (STK11/KEAP1/SMARCA4/CDKN2A) KRAS G12C + STK11 + KEAP1 triple mutants Avoid monotherapy; prioritise combination approaches targeting the PI3K-AKT-mTOR or parallel survival pathways Acquired (on target) Secondary KRAS mutations at SII-P binding residues Y96D/S, H95D/Q/R, G13D, Q99L, R68S RAS(ON) inhibitors (elironrasib, daraxonrasib) Acquired (on target) KRAS G12C allele amplification/ON-state shift 22% of acquired resistance cases; VAF enrichment by ctDNA RAS(ON) inhibitors; ctDNA monitoring Acquired (off target) RTK reactivation (EGFR/HER2/MET) MET amplification; EGFR-driven WT-RAS reactivation Sotorasib + tepotinib; SHP2 inhibitors (RMC-4630, TNO155) Acquired (off target) Downstream mutations (BRAF/MEK/PIK3CA) BRAF V600E; MEK1 mutations; PIK3CA MEK/ERK inhibitors; PI3K-mTOR inhibitors Acquired (off target) Tumour suppressors (NF1/PTEN loss) Constitutive MAPK/PI3K activation Combination with mTOR inhibitors Non-genetic EMT, YAP/TAZ activation, lineage plasticity Scribble relocalisation; histologic transformation MARK2/MARK3 inhibitors; YAP/TEAD inhibitors Non-genetic UPR/IRE1α upregulation PERK upregulation; IRE1α activated post-sotorasib IRE1α-targeting approaches under preclinical/clinical investigation

Intrinsic resistance

Patients with co-mutations in STK11, KEAP1, SMARCA4, or CDKN2A commonly display primary resistance, characterised by progressive disease within 3 months of initiating therapy and poor PFS (Miyashita et al. 2024 ; Rosell et al. 2024 ). These co-mutations activate parallel survival programmes, including epigenetic (SMARCA4), antioxidant (NRF2/KEAP1), and cell-cycle (CDKN2A), that render tumour cells inadequately dependent on KRAS G12C signalling for growth. Low KRAS dependency, where growth is primarily fuelled by PI3K/AKT/mTORC1 or alternative MAPK inputs, is a related intrinsic resistance phenotype refractory like MEK inhibition (Zhu et al. 2022 ). Epigenetic rewiring, oncogene rearrangements (e.g. ALK and RET fusions), and macropinocytosis upregulation can substitute for KRAS-driven growth and further moderate inhibitor efficacy (Zhu et al. 2022 ).

Acquired resistance: on-target mechanisms

Secondary KRAS mutations at residues that disrupt SII-P inhibitor binding are among the most frequently detected acquired resistance mechanisms. Y96D/S, H95D/Q/R, Q99L, and R68S each alter critical contact residues; resistance profiles are partly drug-specific, as H95 variants preferentially affect adagrasib binding, while Y96C reduces sensitivity to both agents (Riedl et al. 2025 ; Awad et al. 2021 ). KRAS G12C allele amplification—reported in approximately 22% of patients with acquired resistance—elevates total KRAS protein levels and shifts the equilibrium toward GTP-loaded active KRAS, counteracting the inhibitory effect (Miyashita et al. 2024 ; Riedl et al. 2025 ; Rosell et al. 2024 ). Serial circulating tumour DNA (ctDNA) analyses have demonstrated that the variant allele frequency of KRAS G12C increases at progression, often accompanied by a shift toward active predominance driven by GEF-mediated GTP reloading (SOS1, RASGEF1B), which outpaces covalent reinhibition (Riedl et al. 2025 ). This biological observation is a primary driver of interest in RAS(ON) inhibitors such as elironrasib (RMC-6291), which targets the active GTP-bound conformation and has exhibited activity in patients who progressed on OFF-state inhibitors (Filis et al. 2025 ).

Acquired resistance: off-target bypass signalling

Upstream RTK reactivation is the most observed off-target resistance mechanism. KRAS G12C inhibition relieves negative feedback on EGFR, HER2, and MET, resulting in RTK ligand-driven reactivation of wild-type RAS isoforms (NRAS, HRAS) in the GTP-bound state, which is inaccessible to current covalent OFF-state inhibitors (Riedl et al. 2025 ; Rosell et al. 2024 ). MET amplification is a particularly actionable bypass event, and its prevalence has justified ongoing clinical evaluation of sotorasib + tepotinib and adagrasib + capmatinib combinations (Rosell et al. 2024 ). Downstream pathway alterations—acquired mutations in BRAF, MEK1, or PIK3CA—can maintain proliferative signalling independently of KRAS, providing an orthogonal bypass that current inhibitors cannot address as monotherapy (Miyashita et al. 2024 ; Riedl et al. 2025 ). Loss-of-function alterations in NF1 (a RAS-GAP) or PTEN (a PI3K suppressor) constitutively activate the MAPK and PI3K-AKT pathways, respectively, and are well-established acquired resistance events (Mohanty et al. 2023 ).

The MRAS:SHOC2:PP1C trimeric phosphatase complex, regulated by HUWE1/Scribble and reactivated by valosin-containing protein (VCP), represents a mechanistically distinct MAPK reactivation node that emerges following sotorasib treatment (Miyashita et al. 2024 ). SHP2 and SOS1 inhibitors are being evaluated clinically to counter both RTK-driven reactivation and SOS1-mediated GTP reloading of wild-type RAS (Hauseman et al. 2025 ; Falchook et al. 2022 ).

Non-genetic and phenotypic resistance

Epithelial-to-mesenchymal transition (EMT) is a rapid, reversible resistance mechanism in which KRAS G12C inhibition triggers a transcriptional programme that reduces KRAS dependency, alters membrane protein organisation (including Scribble complex relocalisation), and activates PI3K signalling as a survival substitute (Ebright et al. 2025 ; Akhave et al. 2021 ; Adachi et al. 2020 ). Histological transformation from adenocarcinoma to squamous cell carcinoma, reflecting extreme lineage plasticity, has been reported under KRAS G12Ci pressure (Lietman et al. 2022 ). YAP/TAZ activation is a convergent resistance node: oncogene-independent YAP signalling maintains cell survival and proliferation after KRAS G12C inhibition, and this has been mechanistically linked to MARK2/MARK3 kinases, which are co-dependencies for YAP/TAZ function across carcinomas (Yang et al. 2024 ; Klingbeil et al. 2024 ). Aquaporin-5 (AQP5), overexpressed in lung cancer and active in EGFR/ERK/p38 MAPK signalling, has also been implicated as a modulator of KRAS G12Ci sensitivity, although clinical evidence remains early (Rosell et al. 2023 ).

Tumour microenvironment and immune remodelling

KRAS G12C inhibitors reshape the tumour immune microenvironment (TME) in ways that are both therapeutically exploitable and potentially resistance-promoting (Molina-Arcas and Downward 2024 ). Adaptive TME changes, such as TGF-β-mediated fibrosis, altered cytokine secretion, and focal adhesion kinase (FAK) activation, can promote tumour cell survival and contribute to resistance (Zhang et al. 2021 ). The immunosuppressive microenvironment associated with STK11 and KEAP1 co-mutations further limits the activity of immunotherapy-based combinations in these subgroups.

Clinical-grade KRAS G12C inhibitors: a global portfolio in rapid evolution

Sotorasib (AMG-510): updated phase 3 data and dosing controversy

Sotorasib (Lumakras/Lumykras, Amgen) received accelerated FDA approval in May 2021 based on the phase 2 CodeBreaK 100 trial, which reported an ORR of 37.1% and mPFS of 6.8 months in previously treated KRAS G12C NSCLC (Skoulidis et al. 2021 ). The 2-year follow-up of CodeBreaK 100 confirmed an ORR of 28.1% by independent review, with a median duration of response of 12.5 months and mOS of 12.5 months (Dy et al. 2023 ).

The definitive phase 3 CodeBreaK 200 trial ( N = 345) randomised patients with previously treated KRAS G12C NSCLC to sotorasib 960 mg daily vs. docetaxel 75 mg/m 2 every 3 weeks. Sotorasib demonstrated a statistically significant improvement in PFS (5.6 vs. 4.5 months; HR: 0.66; 95% CI: 0.51–0.86; p = 0.002) and confirmed ORR (28.1 vs. 13.2%) (de Langen et al. 2023 ). However, the trial failed to display an OS benefit of 10.6 months with sotorasib vs. 11.3 months with docetaxel (HR: 1.01; 95% CI: 0.77–1.33) numerically favouring docetaxel, although the study was not powered for OS and permitted crossover. Although the study supported improved PFS and response rates with sotorasib, the absence of an OS advantage should be interpreted cautiously. The study was powered for PFS rather than OS, indicating that the results more likely reflect the biological limitations of monotherapy than a therapeutic ceiling of KRAS inhibition (de Langen et al. 2023 ). Patient-reported outcomes in CodeBreaK 200 showed that sotorasib maintained quality of life compared with docetaxel (EQ-5D VAS + 2.2 vs. − 5.8 at week 12) (Waterhouse et al. 2024 ).

Data from the CodeBreaK 201 study, which evaluated the efficacy of sotorasib at a post-approval 960 mg dose in comparison with the currently FDA-approved 240 mg dose, showed no statistically significant increase in efficacy with the higher dose. The higher dose exhibited considerably higher rates of hepatotoxicity and gastrointestinal side effects (Hochmair et al. 2024 ). The FDA approved the 960-mg dose, highlighting the importance of dose optimisation in drug development and the challenge of adjusting approved doses once established (Singh et al. 2025 ).

Hepatotoxicity has proven to be a significant hurdle to the combination of sotorasib with immunotherapy. In CodeBreaK 101, the concurrent combination arms, grade 3–4 increases in aminotransferases were seen in up to 75–100% of patients in certain dose levels of the sotorasib–anti-PD-1/PD-L1 combination, thus precluding this combination (Ernst et al. 2024 ). Sotorasib is now being investigated in the first-line setting, primarily in combination with chemotherapy.

Adagrasib (MRTX849): phase 3 confirmation and CNS activity

Adagrasib (Krazati, Mirati/Bristol Myers Squibb) received accelerated FDA approval in December 2022 based on KRYSTAL-1, indicating an ORR of 43% and mPFS of 6.5 months in earlier treated KRAS G12C NSCLC (Jänne et al. 2022 ). Its longer half-life (~ 23 h), higher CNS penetration, and more tolerable combination profile with immunotherapy differentiate it from sotorasib.

The KRYSTAL-12 phase 3 trial ( N = 453) randomised patients with previously treated KRAS G12C NSCLC to adagrasib 600 mg twice daily vs. docetaxel. Results confirmed the superiority of adagrasib across all co-primary and secondary endpoints: mPFS 5.5 vs. 3.8 months (HR: 0.58; 95% CI: 0.45–0.76; p < 0.0001); confirmed ORR 32 vs. 9% (OR: 4.68; p < 0.0001); median duration of response 8.3 vs. 5.4 months; and OS data remain immature (Barlesi et al. 2025 ). Intracranial ORR was 24 vs. 11% for docetaxel, and intracranial median time to progression was 18.6 months with adagrasib. Approximately 40% of patients with KRAS G12C NSCLC develop brain metastases during their disease course; this CNS activity has significant clinical implications and supports the use of adagrasib in patients with active CNS disease (Barlesi et al. 2025 ).

Grade ≥ 3 treatment-related adverse events occurred in 47% of adagrasib-treated patients vs. 46% with docetaxel. Discontinuation due to adverse events was lower with adagrasib (8 vs. 14%), a clinically relevant tolerability advantage. KRYSTAL-12 specifies the most complete confirmatory evidence for a second-generation KRAS G12Ci and supports adagrasib’s conversion from accelerated to full FDA approval (Barlesi et al. 2025 ; Luo and Arter 2024 ).

Next-generation KRAS G12C inhibitors

Divarasib (GDC-6036)

Divarasib (Roche) is 5–20 times more potent and 50 times more selective than first-generation inhibitors in vitro, with optimised SII-P covalent chemistry and improved pharmacokinetics. In a phase 1 trial ( N = 137 NSCLC patients), divarasib at the recommended 400 mg dose determined an ORR of 53.4% (95% CI: 39.9–66.7%) and mPFS of 13.1 months (95% CI: 8.8–NE) (Sacher et al. 2023 ). Long-term follow-up confirmed an ORR of 59.1% and mPFS of 15.3 months at the 400-mg dose. However, interpretation should remain cautious because these findings derive from an early-phase, non-randomised study, and cross-trial comparisons are inherently limited (Sacher et al. 2023 ).

Fulzerasib (IBI351)

Fulzerasib (GenFleet/Innovent Biologics) received National Medical Products Administration (NMPA) approval in August 2024, becoming the third KRAS G12Ci approved globally. In the phase 2 registrational trial ( N = 116), fulzerasib produced an ORR of 49.1% (95% CI: 39.7–58.6%) and mPFS of 9.7 months—the longest single-agent mPFS of any approved KRAS G12Ci at the time of approval (Zhou et al. 2024 ). The STK11 co-mutation biomarker effect was pronounced: ORR 35.7% (STK11-mutated) vs. 63.5% (STK11 wild-type; p = 0.026), providing clinically actionable guidance for patient selection (Zhou et al. 2024 ). Grade ≥ 3 treatment-related adverse events occurred in 41.4% of patients.

Garsorasib (D-1553)

Garsorasib (InventisBio) received NMPA approval in November 2024 for previously treated KRAS G12C NSCLC. Phase 2 registrational data confirmed ORR of 38.7–50% and mPFS of 7.6 months across studies, with a favourable CNS penetration profile reported in CNS-specific cohorts (Ruan et al. 2025 ; Li et al. 2024 ). Both fulzerasib and garsorasib extend the global approved arsenal to four agents and support that the KRAS G12Ci field is no longer limited to Western-approved drugs.

Glecirasib (JAB-21822)

Phase 2 data of glecirasib (Jacobio) reported an ORR of 47.9%, mPFS of 8.2 months, and mOS of 13.6 months in previously treated KRAS G12C NSCLC. Superior CNS penetration has been confirmed in CNS-specific cohorts (Wang et al. 2025 ).

Olomorasib (LY3537982)

Olomorasib (Eli Lilly) is a second-generation covalent SII-P inhibitor with preclinical evidence of > 90% target occupancy at therapeutic doses, designed to achieve deeper and more sustained KRAS G12C inhibition than first-generation agents. In the phase 1/2 LOXO-RAS-20001 trial, olomorasib monotherapy in KRAS G12Ci-naïve patients confirmed an ORR of 63% and DCR of 93% (Burns et al. 2025 ). In combination with pembrolizumab as first-line therapy in treatment-naïve patients ( n = 46), the ORR was 74% (95% CI: 59.8–85.7%), DCR was 91%, and mPFS was not reached at 12-month follow-up, with a 12-month PFS rate of 66.7% (Dragnev et al. 2025 ). In patients with PD-L1 ≥ 50%, ORR reached 85%. Olomorasib in combination with pembrolizumab was reported as first-line therapy in KRAS G12C NSCLC with PD-L1 ≥ 50% (Eli 2025 ). The phase 3 SUNRAY-01 ( NCT06119581 ) and SUNRAY-02 ( NCT06890598 ) trials are evaluating olomorasib across first-line settings with PFS as the primary endpoint (Negrao 2024 ).

HS-10370 and other pipeline agents

HS-10370 (Hansoh Pharma) exhibited an ORR of 51.2% and a mPFS of 11.3 months at the optimal dose in phase 2 data, further validating the superior efficacy profile emerging for next-generation agents. Additional clinical-stage agents such as FMC-376 (dual ON/OFF inhibitor; NCT06244771 ), D3S-001 (rapid target engagement kinetics; NCT05410145 ), MK-1084 (Merck; NCT06345729 ), BBO-8520 (dual GDP/GTP binding; NCT06343402 ), BI-1823911 ( NCT04973163 ), and ALTA-3263 ( NCT06835569 ) are in active phase 1/2 development (Keating 2024 ; Zhang et al. 2024 ; Maciag et al. 2025 ; Waizenegger et al. 2022 ).

RAS(ON) and pan-RAS inhibitors: a conceptually distinct third generation

The active enrichment of KRAS G12C upon progression on inactive inhibitors directly motivates a new mechanistic class targeting the active GTP-bound conformation. These tri-complex inhibitors recruit an endogenous chaperone (cyclophilin A) to physically occlude the effector-binding interface of RAS(ON), preventing downstream signalling regardless of nucleotide state (Filis et al. 2025 ).

Elironrasib (RMC-6291, Revolution Medicines) is an RAS(ON) G12C-specific tri-complex inhibitor. Phase 1 data show activity in patients who progressed on first-generation OFF-state inhibitors, addressing the most critical unmet need in the post-sotorasib/adagrasib treatment space (Nichols et al. 2022 ). Daraxonrasib (RMC-6236, Revolution Medicines) is a non-covalent pan-RAS(ON) inhibitor that targets all active GTP-bound RAS paralogs, including G12C, G12D, G12V, and wild-type isoforms. Pan-RAS inhibition is particularly relevant for NSCLC patients who may harbour multiple KRAS variant subclones or develop alternative KRAS mutations at resistance, and for settings where wild-type RAS isoform reactivation drives bypass signalling.

A critical safety consideration for pan-RAS and pan-KRAS inhibitors is the myeloid toxicity signal observed when KRAS expression is systemically ablated in adult mouse models (Zamorano-Dominguez et al. 2025 ). In pan-KRAS inhibitor-treated models, alongside MAPK suppression, upregulation of LKB1/AMPK targets, including MARK2/MARK3 kinases, was observed; MARK2 overexpression was associated with increased pan-KRAS inhibitor sensitivity, yet downstream MARK2 signalling may paradoxically drive YAP1 upregulation as a late resistance mechanism (McAndrews et al. 2025 ; Meraz et al. 2025 ). Immunohistochemical monitoring of myeloid cell populations in KRAS/pan-RAS inhibitor clinical trials is warranted. Table 2 lists a few reported KRAS G12C inhibitors currently under clinical trials or with regulatory approval. Table 2 KRAS G12C inhibitors with regulatory approval or advanced clinical data Compound name Approval/phase ORR (%) mPFS (months) Key trial/notable feature Sotorasib (AMG-510) FDA full approval 2021 28.1% (Ph3 BICR) 5.6 (Ph3) Improved PFS vs. docetaxel without OS benefit; dose optimisation and hepatoxicity limit immunotherapy combinations Adagrasib (MRTX849) FDA full approval 2022 32% (Ph3) 5.5 (Ph3) Improved PFS and ORR vs. docetaxel; favourable combination profile Fulzerasib (IBI351) China (NMPA) approved 2024 49.1% (Ph2) 9.7 (Ph2) High ORR and longest mPFS among approved agents Garsorasib (D-1553) China (NMPA) approved 2024 38.7–50% (Ph2) 7.6 (Ph2) favourable CNS penetration Divarasib (GDC-6036) Phase 2/3 (Krascendo 1) 53.4–59.1% (Ph1 LTF) 13.1–15.3 (Ph1 LTF) Enhanced potency and selectivity relative to first-gen inhibitors Glecirasib (JAB-21822) Phase 2/3 47.9% (Ph2) 8.2 (Ph2) Favourable efficacy with emerging CNS activity Olomorasib (LY3537982) FDA BTD Sept 2025 74% (1L + pembro) NR (1L + pembro) High first-line activity in PD-L1 ≥ 50% subgroup; Ph3 evaluation ongoing HS-10370 Phase 1 51.2% (Ph2) 11.3 (Ph2) Next-gen SII-P covalent inhibitor Elironrasib (RMC-6291) Phase 1 ongoing NR (early phase) NR RAS(ON) G12C tri-complex inhibitor designed to overcome OFF-state resistance mechanisms Daraxonrasib (RMC-6236) Phase 1 NR NR Pan-RAS(ON) tri-complex inhibitor; myeloid toxicity monitoring required BTD breakthrough therapy designation, NR not reached, LTF long-term follow-up, 1G first-generation inhibitor, BICR blinded independent central review, 1L first-line PD-L1 ≥ 50% refers to the PD-L1 subgroup in the olomorasib + pembrolizumab combination. ORR and mPFS values for fulzerasib, garsorasib, glecirasib, divarasib, olomorasib, HS-10370, and RAS(ON) inhibitors are derived primarily from single-arm phase 1/2 studies and should not be interpreted cautiously across trials

Combination strategies to address resistance pathways

Given the near universality of resistance to monotherapy, rational combinations targeting bypass signalling mechanisms are the central focus of ongoing clinical development (Table 3 ). Table 3 Mechanism-specific combination strategies and translational evidence in KRAS G12C-mutant NSCLC KRAS G12C inhibitor Combination partner(s) Mechanistic rationale Clinical trial status/phase Key clinical outcomes Evidence level/translational priority Adagrasib Pembrolizumab (PD-1) KRAS inhibition increases antigen presentation; ICI synergy KRYSTAL-7 Ph3 ( NCT04613596 ) ORR 44% overall; 59% in PD-L1 ≥ 50% A/high Sotorasib Carboplatin + pemetrexed Chemo-KRAS combo for PD-L1-negative patients CodeBreaK 202 Ph3 ( NCT05920356 ) ORR 65%, DCR 100%, mPFS 10.8 months A/high Olomorasib Pembrolizumab Sustained KRAS G12C inhibition with enhanced immunotherapy activity SUNRAY-01 Ph3 ( NCT06119581 ) ORR 74% overall; 85% in PD-L1 ≥ 50%; mPFS NR B/high Adagrasib or sotorasib SHP2 inhibitors (RMC-4630, TNO155) Suppresses RTK-mediated wild-type RAS reactivation and adaptive GTP reloading Multiple Ph 1/2 (e.g. NCT05054725 ) ORR 50% in G12Ci-naive; limited activity post-G12Ci progression B/medium Adagrasib or sotorasib MET inhibitors (tepotinib, capmatinib) Counter MET amplification bypass resistance Ph 1/2 combination studies Biomarker-directed strategy for MET-amplified bypass resistance B/medium Adagrasib or sotorasib MEK/ERK inhibitors Downstream blockade of BRAF/MEK bypass mutations Ph 1 combination cohorts Preliminary pathway suppression observed; clinical activity limited by tolerability B/exploratory Adagrasib or sotorasib PI3K/AKT/mTOR inhibitors Orthogonal PI3K-AKT bypass when MAPK is inhibited Exploratory Ph 1/2 Preclinical activity in resistant KRAS models C/exploratory Evidence levels were assigned according to the highest level of supporting evidence: grade A, phase III clinical evidence; grade B, phase I/II or translational clinical evidence; grade C, preclinical/mechanistic evidence. Translational priority reflects current clinical feasibility and the likelihood of near-term phase clinical implementation

RTK/upstream targeting

RTK reactivation is the dominant adaptive resistance mechanism, and co-inhibition of EGFR (cetuximab, erlotinib), MET (tepotinib, capmatinib), or pan-HER (neratinib) together with KRAS G12C inhibitors is in active clinical evaluation. Sotorasib + tepotinib, informed by preclinical data revealing synergy in MET-amplified KRAS G12C models, is a particularly advanced combination (Rosell et al. 2024 ). SHP2 inhibitors (RMC-4630, TNO155) block RTK-to-RAS signal transduction and KRAS GTP reloading by wild-type isoforms; CodeBreaK 101 data showed an ORR of 50% with sotorasib plus RMC-4630 in KRAS G12Ci-naïve NSCLC but no responses in patients with prior G12C inhibition (Falchook et al. 2022 ). SOS1 inhibitors (BI 1701963) disrupt nucleotide exchange and have been evaluated with adagrasib in phase 1b trials (Hauseman et al. 2025 ; Luo and Arter 2024 ).

Downstream pathway blockade

Acquired downstream mutations in BRAF, MEK, and PIK3CA are targetable with MEK (trametinib, binimetinib), BRAF (dabrafenib), or PI3K inhibitors (alpelisib, copanlisib). CRISPR-Cas9 knockout and pharmacological inhibition of PI3K restore sotorasib sensitivity in resistant cell lines; dual mTORC1/2 inhibitors (AZD8055, sapanisertib) restore sensitivity specifically through 4E-BP1 dephosphorylation (Jänne et al. 2025 ).

Immune checkpoint inhibitors

KRAS G12C inhibition upregulates MHC-I and enhances tumour-infiltrating T cell infiltration, providing a biological rationale for ICI combination (Molina-Arcas and Downward 2024 ). Adagrasib and olomorasib have tolerable combination profiles with pembrolizumab, while sotorasib is hepatotoxic in concurrent ICI combinations (Waizenegger et al. 2022 ). KRYSTAL-7 phase 2 (first-line adagrasib + pembrolizumab) confirmed an ORR of 44% in treatment-naïve KRAS G12C NSCLC across all PD-L1 levels ( n = 149), with an ORR of 59% in the PD-L1 ≥ 50% subgroup; the phase 3 portion vs. pembrolizumab monotherapy is ongoing ( NCT04613596 ) (Molina-Arcas and Downward 2024 ; Garassino et al. 2025 ).

To improve translational applicability, combination strategies were stratified according to the level of clinical evidence and translational maturity (Table 3 ). Immune checkpoint inhibitors and chemotherapy-based combinations currently possess the strongest clinical support, while MEK/ERK- and PI3K/AKT/mTOR-directed approaches remain exploratory due to limited clinical validation and toxicity concerns.

First-line treatment strategies

The failure of sotorasib to prove OS benefit in the second-line setting, combined with maturing first-line data signifying substantially higher response rates when KRAS G12C inhibitors are used earlier, has made the first-line positioning question the dominant clinical debate in this field. Multiple registrational phase 3 trials are now directly testing this hypothesis, stratified by PD-L1 expression and co-mutation status (Table 4 ). Table 4 Mechanism-stratified drug repurposing strategies for KRAS G12C NSCLC Drug Original indication Resistance pathway targeted KRAS G12C-specific mechanism/translational priority (TP) Evidence grade/clinical translational status Statins (lovastatin, simvastatin) Hypercholesterolaemia KRAS membrane localisation Inhibits the mevalonate pathway and disrupts KRAS membrane localisation (TP-medium) Grade B (observational + preclinical) (Doumat et al. 2023 ) Itraconazole Antifungal EMT/Hedgehog resistance; VEGFR2 Suppresses EMT and VEGFR2 signalling (TP-medium) Grade B (early clinical evaluation) (Mohamed et al. 2021 ; Rudin et al. 2013 ) Hydroxychloroquine Antimalarial Autophagy-mediated resistance Blocks adaptive autophagy-associated survival pathways (TP-medium) Grade B (early clinical evaluation) (Malhotra et al. 2019 ; Aggarwal et al. 2023 ) Metformin Type 2 diabetes PI3K-AKT-mTOR bypass; metabolic reprogramming Modulates AMPK, suppresses mTORC1, and glycolysis (TP-medium) Grade B (translational evidence) (Viveiros et al. 2019 ; Arrieta et al. 2019 ) Auranofin Rheumatoid arthritis Oxidative stress/ROS management Proposed modulation of oxidative stress pathways (TP-low) Grade C (exploratory preclinical ROS-targeting) (Doumat et al. 2023 ) Disulfiram Anti-alcoholism Proteasome/NF-κB Proteostasis disruption in KRAS-driven models (TP-medium) Grade B (early clinical) (Nechushtan et al. 2015 ) A485 p300 inhibitors: investigational (preclinical) Glycolytic/metabolic reprogramming Inhibits p300, suppresses metabolic rewiring (TP-low) Grade C (preclinical epigenetic/metabolic) (Wang et al. 2025 ) Nelfinavir HIV-1 protease inhibitor Proteotoxic stress Proposed ER stress-targeting combination strategy (TP-medium) Grade B (early clinical evaluation) (Rengan et al. 2019 ) Clarithromycin (CAM) Macrolide antibiotic TME/inflammatory resistance Inhibits NF-κB and reduces pro-tumour cytokines; prevents KM-LUAD in KRAS G12C mouse model (TP-low) Grade C (preclinical inflammatory) (Deng et al. 2026 ) Ganetespib HSP90 inhibitor (investigational oncology) Chaperone-mediated KRAS stabilisation Disrupts HSP90 and destabilises KRAS signalling proteins (TP-high) Ph II; grade A (clinical evidence for KRAS) (Socinski et al. 2013 ) Dasatinib + osimertinib TKI for CML + 3rd-gen EGFR-TKI Bypass signalling/SRC kinase resistance Blocks SRC-mediated bypass signalling (TP-high) Ph I/II; grade B (early clinical evaluation of bypass/SRC resistance targeting) (Song et al. 2024 ) Minocycline Tetracycline antibiotic Chemoradiation-related inflammation/NF-κB Inhibits NF-κB-mediated fibrosis signalling (TP-medium) Ph II; grade B (Early clinical evaluation for TME modulation) (Wang et al. 2020 ) Pirfenidone + chemotherapy Anti-fibrotic (idiopathic pulmonary fibrosis) TGF-β-mediated fibrotic resistance/TME remodelling Inhibits TGF-β and PDGF signalling (TP-medium) Ph I; grade B (early clinical evaluation of fibrosis) (Yamamoto et al. 2020 ) Quinacrine + erlotinib Antimalarial + EGFR-TKI NF-κB/FACT complex inhibition Inhibits FACT and NF-κB, suppresses pro-tumour inflammatory signalling (TP-medium) Ph I; grade B (early clinical evaluation of epigenetic modulation) (Dermawan et al. 2014 ) Romidepsin + erlotinib HDAC inhibitor (T cell lymphoma) + EGFR-TKI Epigenetic reprogramming/HDAC-mediated resistance Inhibits HDAC, restoring epigenetic resistance (TP-medium) Ph I; grade B (early clinical evaluation of epigenetic resistance targeting) (Gerber et al. 2015 ) Gefitinib + bevacizumab EGFR-TKI + anti-VEGF antibody Angiogenic bypass/VEGF-driven resistance Dual EGFR/VEGF blockade counters VEGF-mediated escape from EGFR inhibition (TP-high) Ph II; grade A (clinical evidence of angiogenic bypass targeting) (Kitagawa et al. 2019 ) Atovaquone Antimicrobial (malaria/PCP prophylaxis) Tumour hypoxia/mitochondrial complex III Inhibits mitochondrial complex III, reduced hypoxia (TP-medium) Ph I; grade B (early clinical evaluation of hypoxia) (Arrieta et al. 2019 ) Vancomycin + SBRT Glycopeptide antibiotic Gut microbiome modulation/immune priming Modulates microbiome-mediated immune priming (TP-low) Early Ph I; grade C (exploratory microbiome-mediated immune priming strategy) (Prezzano et al. 2019 ) Dexamethasone Corticosteroid Estrogen-mediated/epigenetic resistance Induces oestrogen sulfotransferase, re-sensitises PD-1-refractory tumours through senescence induction (TP-medium) Ph I/II; grade B (early clinical evaluation of epigenetic resistance modulation) (Wang et al. 2016 ) Selinexor (+ docetaxel) XPO1/nuclear export inhibitor (multiple myeloma, lymphoma) Nuclear export-mediated resistance/KRAS-mutant dependency Inhibits XPO1-mediated nuclear export, retains tumour suppressor activity (TP-low) Ph I/II; grade C (exploratory synthetic lethality strategy) (von Itzstein et al. 2025 ) Prednisone + afatinib Corticosteroid + 2nd-gen EGFR-TKI Inflammatory cytokine/immune-mediated resistance Suppresses inflammatory cytokine signalling (TP-medium) Ph II; grade B (early clinical evaluation of immune-mediated resistance) (Doumat et al. 2023 ) SBRT stereotactic body radiation therapy, HDAC histone deacetylase, HSP90 heat shock protein 90, ER oestrogen receptor, KM-KUAD KRAS-mutant lung adenocarcinoma, FACT facilitates chromatin transcription complex, IPF idiopathic pulmonary fibrosis, XPO1 exportin-1, TME tumour microenvironment Evidence grading: grade A: clinical evidence (phase II/III or KRAS G12C-specific studies); grade B: early clinical or translational evidence with KRAS-mutant relevance; grade C: preclinical/mechanistic rationale only. Translation priority (TP) indicates clinical actionability: high, near-term clinical potential; medium, early translational potential; low, exploratory

Rationale for first-line KRAS G12Ci use

The biological rationale for earlier KRAS G12Ci use is multifactorial. First, STK11 and KEAP1 co-mutations, present in approximately 34 and 16% of KRAS G12C cases, respectively, predict poor immunotherapy responses but retain meaningful KRAS G12Ci sensitivity, making these patients suboptimal candidates for pembrolizumab-based standard first-line regimens (Skoulidis et al. 2025 ). CodeBreaK 201 is directly testing sotorasib monotherapy as first-line treatment in patients with PD-L1 < 1% and/or STK11 mutation ( NCT04933695 ). Second, pre-treatment tumours have a simpler resistance landscape, less clonal evolution, and may respond more durably to KRAS G12C inhibition before bypass mechanisms have been selected for (Oya et al. 2024 ).

Sotorasib first-line combinations

CodeBreaK 101 evaluated sotorasib in combination with carboplatin and pemetrexed as first-line therapy. Updated analysis reported an ORR of 65%, DCR of 100%, and mPFS of 10.8 months overall (11.9 months in PD-L1-negative patients)—a substantial improvement over second-line monotherapy (Li et al. 2024 ). The SCARLET study (Japan) evaluated the same combination and reported final analysis results of ORR 88.9%, mPFS 6.6 months, and mOS 20.6 months, notably a high ORR achieved at the cost of somewhat shorter PFS relative to CodeBreaK 101, potentially reflecting patient population differences (Yoshioka et al. 2024 ). Based on these data, CodeBreaK 202 ( NCT05920356 ) is a phase 3 global registrational trial comparing sotorasib + carboplatin-pemetrexed vs. pembrolizumab + carboplatin-pemetrexed in patients with PD-L1-negative KRAS G12C NSCLC (Barlesi et al. 2024 ). Sotorasib-ICI concurrent combinations are not pursued due to prohibitive hepatotoxicity.

Adagrasib first-line combinations

Adagrasib establishes a more tolerable interaction with pembrolizumab than sotorasib, enabling ICI-based first-line combinations. Updated KRYSTAL-7 phase 2 data ( n = 149 across all PD-L1 levels) reported an ORR of 44% in treatment-naïve KRAS G12C NSCLC, with an ORR of 59% in the PD-L1 ≥ 50% subgroup (Molina-Arcas and Downward 2024 ; Garassino et al. 2025 ). The phase 3 portion (adagrasib + pembrolizumab vs. pembrolizumab monotherapy in PD-L1 ≥ 50%) is ongoing ( NCT04613596 ), with results anticipated in 2026 (Garassino et al. 2025 ). KRYSTAL-1 Cohort E evaluated adagrasib monotherapy as first-line therapy specifically in patients with STK11 mutations—a subgroup underserved by immunotherapy. Results showed an ORR of 30.3% and mPFS of 4.8 months, with mOS of 12.3 months, providing support for KRAS G12Ci use in this biomarker-selected population (Molina-Arcas and Downward 2024 ).

Olomorasib: breakthrough therapy for first-line PD-L1-high disease

As described in “Next-generation KRAS G12C”, the olomorasib + pembrolizumab combination has established exceptional first-line activity—ORR 74% overall and 85% in PD-L1 ≥ 50% patients—forming the basis for FDA Breakthrough Therapy Designation for first-line KRAS G12C NSCLC with PD-L1 ≥ 50% in September 2025 (Dragnev et al. 2025 ; Eli 2025 ). SUNRAY-01 is a double-blind phase 3 study comparing olomorasib + pembrolizumab (with or without chemotherapy) vs. placebo + standard-of-care in treatment-naïve KRAS G12C-mutant NSCLC. Part A (PD-L1 ≥ 50%) and part B (all PD-L1 levels with chemotherapy) are both enrolling globally ( NCT06119581 ). SUNRAY-02 evaluates olomorasib + immunotherapy in resectable disease and unresectable locally advanced NSCLC ( NCT06890598 ) (Negrao et al. 2024 ).

Biomarker-guided first-line treatment selection

The emerging first-line data support a biomarker-stratified treatment algorithm. In patients with KRAS G12C NSCLC and PD-L1 ≥ 50% without STK11/KEAP1 co-mutations, pembrolizumab monotherapy remains a current standard; however, the olomorasib + pembrolizumab combination (if SUNRAY-01 is positive) and adagrasib + pembrolizumab (if KRYSTAL-7 is positive) may substantially change this paradigm. In patients with PD-L1 < 1% or STK11/KEAP1 co-mutations—where pembrolizumab-based regimens are least effective—sotorasib + chemotherapy (CodeBreaK 202 if positive) or adagrasib-based combinations represent logical alternatives. Patients with brain metastases should be considered preferentially for adagrasib or olomorasib given their CNS penetration profiles.

Drug repurposing: an emerging approach

Conventional de novo drug discovery requires 12–15 years and an estimated $1.24 billion per approved compound, with a historical success rate of approximately 5% for oncology agents entering phase 1 trials (Gil and Martinez 2021 ). Drug repurposing, the application of approved agents with established safety profiles to new indications, offers a more rapid and cost-effective pathway to expanding the therapeutic armamentarium for KRAS G12C NSCLC. Critically, the growing understanding of KRAS G12C resistance mechanisms provides a rational mechanistic framework for repurposing: each resistance pathway defines a set of candidate complementary agents whose existing pharmacology directly addresses the bypass mechanism (Fig. 2 ) (Ruiz et al. 2020 ). Rather than cataloguing repurposed drugs by drug class alone, we organise the evidence according to the resistance pathway each agent targets within KRAS G12C biology—providing a mechanistically actionable framework for combination design (Table 4 ). For the above-mentioned reasons, repurposing gives the old, existing drugs new indications in the present “target-rich, lead-poor” scenario of drug discovery. Fig. 2 Comparison of the de novo drug discovery timeline with the drug repurposing timeline. Rationale for drug repurposing as a near-term strategy to address KRAS G12Ci resistance. Created in Microsoft PowerPoint 360

Category A: targeting KRAS membrane localisation and processing

Statins (HMG-CoA reductase inhibitors)

KRAS requires farnesylation, a post-translational lipid modification produced by the mevalonate pathway, for plasma membrane anchoring and oncogenic signalling. Statins inhibit HMG-CoA reductase, the rate-limiting mevalonate pathway enzyme, depleting farnesyl pyrophosphate and impairing KRAS membrane localisation. Population-based studies associate statin use with improved survival in KRAS-mutant NSCLC, and preclinical studies show synergy between statins and direct KRAS G12C inhibitors in cell lines and xenograft models. An observational NCT05636592 study is evaluating statins + PD-1/PD-L1 inhibitors in early-stage NSCLC (Doumat et al. 2023 ). The mevalonate pathway has emerged as a convergent resistance node in KRAS G12C NSCLC. TP53 mutations present in approximately 50% of KRAS G12C mutant tumours directly upregulate squalene epoxidase (SQLE), a downstream mevalonate pathway enzyme. ARID1A co-mutations seen in around 30% of NSCLC activate 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) via the mevalonate programme. XBP1, which is transcriptionally upregulated by sotorasib therapy, independently drives mevalonate gene expression and downstream YAP1 activation. Together, these convergent mechanisms nominate the mevalonate pathway and its downstream effector YAP1 as a pan-resistance target in KRAS G12C NSCLC that can be addressed with simvastatin or other HMGCR inhibitors in rationally designed combination trials (Ruiz et al. 2020 ; Gui et al. 2025 ; Zhong et al. 2026 ).

Itraconazole

Originally an antifungal agent, itraconazole inhibits the Hedgehog signalling pathway and VEGFR2, both of which are implicated in EMT-driven resistance to KRAS G12C inhibitors. Phase 2 clinical data in advanced NSCLC ( NCT03664115 ) supported disease control in a subset of patients receiving itraconazole + platinum-based chemotherapy (Mohamed et al. 2021 ). Itraconazole has also been evaluated as second-line therapy in combination with pemetrexed ( NCT00769600 ) (Rudin et al. 2013 ).

Terbinafine

An FDA-approved oral antifungal that inhibits SQLE. In H358 KRAS G12C NSCLC xenograft models, sequential omeprazole priming followed by terbinafine + fulzerasib produced superior tumour growth inhibition compared with single-agent treatment, consistent with cholesterol pathway sensitisation enhancing KRAS inhibitor efficacy.

Category B: targeting bypass signalling pathways

Hydroxychloroquine (autophagy inhibitor)

KRAS-mutant cancers upregulate autophagy as a survival mechanism under metabolic stress and targeted therapy pressure. Hydroxychloroquine inhibits lysosomal acidification and blocks autophagosome fusion, sensitising KRAS-mutant cells to cytotoxic and targeted therapy. Phase 1/2 data ( NCT01649947 ) evaluated hydroxychloroquine + chemotherapy in KRAS-mutant NSCLC. Binimetinib + hydroxychloroquine was evaluated in a phase 2 trial ( NCT04735068 ) specifically in advanced KRAS-mutant NSCLC, targeting autophagy as a MEK inhibitor resistance mechanism (Malhotra et al. 2019 ; Aggarwal et al. 2023 ). Lysosomal blockade by chloroquine disrupts the LDL/lipoprotein cholesterol recycling loop, impairs sterol regulatory element-binding protein 1 (SREBP) cleavage-activating protein (SCAP-SREBP1) trafficking from the ER to the Golgi, and consequently suppresses downstream lipogenic gene expression, including SQLE and fatty acid synthase (FASN), that sustains mevalonate pathway activity and YAP1 signalling (Ruiz et al. 2020 ; Gui et al. 2025 ; Zhong et al. 2026 ; Mohamed et al. 2021 ; Rudin et al. 2013 ; Malhotra et al. 2019 ; Aggarwal et al. 2023 ; Olmo-González et al. 2026 ; Viveiros et al. 2019 ; Arrieta et al. 2019 ; Skwarski et al. 2021 ; Dermawan et al. 2014 ; Nechushtan et al. 2015 ).

Metformin (AMPK activator)

As a biguanide antidiabetic, metformin activates AMPK, which suppresses mTORC1, a major bypass signalling node in KRAS G12Ci resistance. AMPK activation also interferes with aerobic glycolysis, on which KRAS-mutant cells depend for proliferation. Population-based analyses explain improved outcomes in diabetic patients with KRAS-mutant cancers receiving metformin. Phase 2/3 clinical trials include metformin + nivolumab in NSCLC ( NCT03048500 ) and metformin + tyrosine kinase inhibitors in EGFR-mutant NSCLC ( NCT05445791 ) [72, 73]. Metformin’s outstanding safety profile and negligible cost make it a high-priority repurposing candidate for combination with KRAS G12C inhibitors.

Digoxin and cardiac glycosides (HIF-1α suppression)

KRAS G12C-resistant cells under hypoxic conditions upregulate HIF-1α-driven survival programmes. Cardiac glycosides inhibit HIF-1α synthesis and have proved anti-tumour activity in KRAS-driven preclinical models. While no KRAS G12C-specific clinical trial data exist, this class merits consideration in combination designs targeting hypoxic resistance (Skwarski et al. 2021 ).

Category C: tumour microenvironment and immune modulation

Aspirin and COX-2 inhibitors (NF-κB suppression)

KRAS mutations activate NF-κB, which drives PD-L1 upregulation and immunosuppressive cytokine secretion in the TME. COX-2 inhibition reduces prostaglandin E2 production, which suppresses T cell activity in the TME. Aspirin and COX-2 inhibitors thus theoretically sensitise immunologically cold KRAS G12C tumours (particularly STK11-mutated tumours) to immune checkpoint inhibitors. Clinical evaluation in colorectal KRAS-mutant cancers provides proof of concept; NSCLC-specific KRAS G12C trials are warranted (Dermawan et al. 2014 ).

Disulfiram (proteasome inhibitor)

An anti-alcoholism drug, disulfiram, inhibits the proteasome and NF-κB signalling while activating apoptotic pathways selectively in cancer cells. A phase 2/3 trial ( NCT00312819 ) evaluated disulfiram + chemotherapy in metastatic NSCLC (Nechushtan et al. 2015 ).

Auranofin (thioredoxin reductase inhibitor)

It is approved for rheumatoid arthritis, which inhibits thioredoxin reductase (TrxR) and disrupts the thioredoxin-dependent ROS management system. KRAS-mutant cancer cells upregulate thioredoxin pathway activity to manage elevated ROS generated by oncogenic signalling. Auranofin exploits this dependency, causing lethal ROS accumulation in KRAS-driven tumour cells (Andreani et al. 2025 ).

Category D: targeting the GAPDH succinylation and metabolic reprogramming axis

Tobacco smoking, the primary aetiological factor in KRAS G12C NSCLC, promotes tumour progression through GAPDH K251 succinylation, catalysed by the acetyltransferase p300. This modification rewires glycolytic metabolism to support tumour cell survival. Wang et al. reported that GAPDH K251 succinylation is reduced by the p300 acetyltransferase inhibitor A485, and, in a KRAS G12D mouse model, GAPDH K251 succinylation promoted glycolysis for tumour cell energy generation (Wang et al. 2025 ). A485 and related compounds represent an emerging repurposing avenue specifically motivated by the smoking-associated biology of KRAS G12C NSCLC.

Category E: antibiotic, antiparasitic, and nuclear export agents: microbiome, TME, and KRAS-selective reprogramming

Clarithromycin (CAM), a macrolide antibiotic approved for bacterial infections and Helicobacter pylori eradication, has emerged as a promising repurposing candidate for KRAS‑mutant lung adenocarcinoma (KM‑LUAD). CAM decreased Gr1⁺ neutrophil and PMN‑MDSC infiltration, suppressed pro‑tumour cytokines (IL‑6, TNF‑α, IL‑1β), and downregulated M2 macrophage markers (arginase‑1, Fizz1). It also remodelled the gut microbiome by increasing the beneficial genus Muribaculaceae and reducing Desulfovibrio , collectively shifting the inflammatory and immunologic milieu toward an anti‑tumour state. Through these coordinated effects on the tumour microenvironment, cytokine signalling, and the gut–lung axis, and given its oral availability, low cost, and established safety, CAM warrants prioritisation for clinical chemoprevention trials in high-risk KRAS-mutant NSCLC patients (Deng et al. 2026 ).

Selinexor is an FDA‑approved XPO1 inhibitor that has reported selective activity in KRAS‑mutant NSCLC. In a phase I/II trial, selinexor + docetaxel showed clinical activity in previously treated KRAS‑mutant patients, including those who had received chemotherapy, immunotherapy, or KRAS G12C inhibitors. Selinexor blocks XPO1 and keeps tumour suppressors such as p53, p21, and FOXO in the nucleus, thereby activating tumour suppressor pathway and is applicable to non-G12C variants and post-KRAS inhibitor resistance (von Itzstein et al. 2025 ). Atovaquone, an antimicrobial agent, inhibits mitochondrial complex III by improving tumour oxygenation. The phase 1 data confirm increased oxygenation in locally advanced NSCLC (Skwarski et al. 2021 ).

Computational and AI-assisted drug repurposing

The high-resolution KRAS G12C crystal structure (available in the Protein Data Bank since 2019) has enabled large-scale virtual screening of FDA-approved drug libraries for compatibility with the SII-P binding pocket and allosteric sites on KRAS G12C. Machine learning models integrating structural and transcriptomic data have identified several clinically approved compounds with predicted off-target KRAS binding. KRAS G12C’s reactive cysteine also makes it amenable to covalent virtual screening approaches, narrowing the field of candidates from thousands to a tractable number of leads. Combining AI-driven virtual screening with experimental validation in patient-derived organoids (“ Advanced technologies and 3D models in KRAS G12C research ”) represents the most efficient contemporary repurposing workflow.

Clinical translational roadmap

To enhance clinical applicability, repurposing strategies were prioritised according to evidence strength, biological rationale, and feasibility for clinical translation. The inhibitors supported by KRAS G12C NSCLC-specific clinical evidence or phase I/II studies were classified as grade A–B (high translational priority). This included RTK/SHP2 signalling, combinations targeting immune modulation, metabolic modulations, and TME pathways, representing the most promising candidates for near-term clinical evaluation in KRAS G12C-resistant NSCLC. In contrast, strategies supported primarily by mechanistic rationale or preclinical models were classified as grade C, which included epigenetic regulators, ferroptosis-inducing approaches, and computationally derived repurposing candidates. Integration of serial ctDNA monitoring, co-mutation profiling, and adaptive trial designs can facilitate progression from mechanistic observations to clinically actionable interventions.

Advanced technologies and 3D models in KRAS G12C research

3D spheroid and organoid models

Traditional two-dimensional cell cultures incompletely recapitulate the spatial architecture, nutrient and oxygen gradients, cell–cell interactions, and drug penetration barriers of solid tumours in vivo. Three-dimensional culture systems, including tumour spheroids, patient-derived organoids (PDOs), and microfluidic organ-on-chip platforms, provide substantially more clinically predictive models for drug efficacy and resistance testing (Urzì et al. 2023 ; Lee et al. 2024 ).

Patient-derived organoids for lung cancer are generated directly from primary resection or biopsy material and preserve the histological, genetic, and functional heterogeneity of the parental tumour, including KRAS G12C mutation status and co-mutation context (Lee et al. 2024 ). Studies have reported 73–100% concordance between somatic mutations in patient tissue and corresponding PDOs, enabling individualised drug sensitivity testing prior to clinical decision-making. Adagrasib evaluated in KRAS G12C-mutant spheroids determines concentration-dependent decreases in spheroid diameter and cell viability, in contrast to KRAS wild-type controls; KRAS inhibitors in 3D models consistently show greater activity than in 2D assays, suggesting that spatial architecture amplifies oncogene dependency (Akhave et al. 2021 ; Koga et al. 2021 ).

Organ-on-chip microfluidic devices extend the physiological relevance of 3D models by incorporating vascular flow, mechanical shear stress, and immune cell infiltration dynamics that static organoids cannot replicate. These platforms are particularly valuable for modelling KRAS G12Ci interactions with immune effector cells in the context of combination immunotherapy design. AI-integrated high-content imaging of organoid treatment responses is now being applied to compound library screening, creating a pipeline from in silico target identification through organoid validation to clinical prioritisation.

Neoadjuvant clinical trials using KRAS G12C inhibitors in resectable NSCLC ( NCT05118854 using sotorasib; NCT05472623 using adagrasib; NCT04302025 using divarasib; NCT05714891 using opnurasib) provide a unique opportunity to generate pre- and post-treatment tumour samples for 3D model construction and spatial transcriptomic analysis (Barlesi et al. 2024 ). These trials also enable minimal residual disease (MRD) monitoring via ctDNA, linking molecular response depth to surgical outcomes.

CRISPR-Cas9 functional genomics

Genome-wide CRISPR/Cas9 dropout screens have identified synthetic lethal interactions specific to KRAS G12C inhibition, providing a systematic catalogue of co-vulnerabilities. The ABCC1 (MRP1) transporter was identified as a critical mediator of adagrasib resistance in KRAS G12C NSCLC; its inhibition by SRC inhibitors (dasatinib, bosutinib) synergistically enhanced adagrasib activity in PDOs (Wang et al. 2020 ). Combined CRISPR screens for KRAS G12C plus SHP2 inhibitor combinations have identified resistance mechanisms specific to this combination, enabling rational third-agent design (Prahallad et al. 2023 ). CRISPR screens in STK11/KEAP1-comutated KRAS G12C cells are a priority, given that these patients have the greatest unmet need and the fewest therapeutic options.

Single-cell spatial transcriptomics

Single-cell spatial transcriptomics applied to longitudinal biopsies (pre-treatment, on-treatment, and at progression) from KRAS G12Ci trials has revealed the heterogeneous adaptive programmes underlying resistance. Spatial resolution enables mapping of resistant clone geography within tumours, critical because bulk sequencing conflates signals from cells in different microenvironmental compartments and misses rare subclone populations (Molina-Arcas and Downward 2024 ). These technologies identify adaptive cell states that develop under therapy, including mesenchymal, quiescent, and metabolically reprogrammed subpopulations, providing targets for combination agents. The neoadjuvant trial platform ( NCT05118854 , NCT05472623 ) is particularly well-suited to this analysis, given access to on-treatment tissue.

Circulating tumour DNA and liquid biopsy

ctDNA functions as a real-time, non-invasive biomarker for treatment response monitoring and early resistance detection. Serial ctDNA measurement during KRAS G12Ci therapy enables detection of resistance mutations—secondary KRAS mutations (Y96D, H95R), RTK amplifications (MET, EGFR), and downstream alterations—before radiological progression, allowing prospective treatment modification (Costa et al. 2024 ). In the adagrasib + cetuximab colorectal cancer trial, ctDNA clearance of the KRAS G12C allele was significantly greater with the combination than with adagrasib monotherapy, demonstrating ctDNA as a pharmacodynamic biomarker (Koga et al. 2021 ). MRD monitoring via ctDNA in neoadjuvant KRAS G12Ci trials ( NCT05118854 , NCT05472623 ) represents the frontier of ctDNA application in this disease, potentially enabling adjuvant treatment decision-making guided by residual molecular disease.

Proteomics and phosphoproteomics

Proteomic and phosphoproteomic analyses of KRAS G12C-treated tumour samples and resistant cell models have identified distinct protein expression signatures characterising resistance states, including KRAS G12C reactivation, mTORC1 upregulation, and PI3K/AKT activation (Jänne et al. 2025 ; Koga et al. 2021 ). Integration of phosphoproteomic data with genomic and transcriptomic profiles—proteogenomics—identifies post-translational vulnerabilities that are invisible to DNA-level analysis, including kinase activation patterns that define druggable combination targets. Liu et al. reported that proteomic subset analysis of KRAS-mutant cancers identifies a subset with the poorest prognosis specifically responsive to combined SHP2 and DOT1L inhibition (Liu et al. 2021 ).

Translational challenges, future directions, and clinical implications

Two phase 3 trials have clarified the limits of second‑line KRAS G12Ci monotherapy: sotorasib improved PFS but not OS in CodeBreaK 200, while adagrasib outperformed docetaxel in KRYSTAL‑12 for PFS and ORR. Rather than a ceiling, these results define the beginning point for mechanism‑driven combination therapy (de Langen et al. 2023 ; Barlesi et al. 2025 ). Resistance pathways emerging from these trials, which include RTK reactivation, PI3K-AKT bypass, ON‑state KRAS enrichment, EMT/YAP1 signalling, and UPR activation, represent actionable targets. An equally convergent vulnerability is the mevalonate pathway–YAP1 axis: TP53 co-mutations upregulate SQLE, ARID1A activates HMGCR, and XBP1 further amplifies mevalonate gene expression, with all three routes culminating in YAP1 activation as a shared resistance effector. Progress depends on matching combinations to resistance biology using serial ctDNA, spatial transcriptomics, and patient‑derived organoids. For example, SHP2 co‑inhibition has produced a 50% ORR in G12Ci‑naïve patients; the PI3Kα‑RBD inhibitor BBO‑10,203 demonstrates selectivity in STK11/KEAP1‑comutated tumours; and IRE1α inhibition (e.g. ORIN1001) has emerged as a cross‑pathway resistance node warranting accelerated development (Falchook 2022 ; Simanshu et al. 2025 ; Lv et al. 2023 ; Xu et al. 2024 ). STK11 alterations predominantly promote immune-cold phenotypes characterised by reduced T cell infiltration, while KEAP1 mutations activate NRF2-dependent antioxidant and metabolic programmes that facilitate treatment resistance. Additional strategies, including LZTR1‑stabilising molecular glues that drive KRAS degradation and next‑generation pan‑KRAS inhibitors (BI‑2493), expand the therapeutic toolkit beyond allele‑specific covalent inhibitors (McAndrews et al. 2025 ; Dharmaiah et al. 2025 ).

Prolonged use of OFF‑state KRAS G12C inhibitors leads to enrichment of ON‑state tumour cells, a resistance shift that first‑generation covalent inhibitors cannot overcome. RAS(ON) tri‑complex inhibitors directly address this gap, including elironrasib (RMC‑6291) (Nichols 2022 ), which has shown activity post-progression on first‑generation agents, and daraxonrasib (RMC‑6236) (Filis et al. 2025 ), which extends this approach with pan‑RAS(ON) activity covering multi‑subclone and wild‑type RAS‑driven bypass. CNS progression also requires specific consideration, as ~ 40% of patients develop brain metastases; adagrasib delivers the strongest intracranial data to date, with olomorasib also exhibiting meaningful CNS penetration (Barlesi et al. 2025 ; Dragnev et al. 2025 ). Finally, mechanism‑based drug repurposing remains a practical near‑term strategy, with well‑characterised agents such as statins, metformin, clarithromycin, auranofin, and selinexor suitable for rapid integration into combination studies (Doumat et al. 2023 ; Olmo-González et al. 2026 ; Deng et al. 2026 ; von Itzstein et al. 2025 ).

Future clinical trials should integrate advanced diagnostic techniques such as ctDNA monitoring for early detection of emerging resistance clones and patient-derived organoid platforms for rapid functional testing of therapeutic combinations. Adaptive biomarker-stratified trial designs evaluating OFF-state inhibitors, RAS(ON) inhibitors, and mechanism-based repurposed agents together may provide a practical route toward durable disease control and personalised therapeutic sequencing.

Conclusion: toward durable responses in KRAS G12C-mutant NSCLC

Five years ago, the KRAS G12C mutation in NSCLC was effectively a dead end therapeutically. Now, there are four approved inhibitors, a growing roster of clinical-stage agents, and several phase 3 first-line trials in progress which is a transformation that few fields have achieved in such a short time. Nevertheless, sustaining that momentum demands facing the limitations of monotherapy. Precision-matched combinations based on resistance mechanisms, guided in real time by ctDNA, assessed in patient-derived organoids, and administered to patients chosen based on their actual tumour biology rather than general eligibility criteria, will be key to moving from short-term disease control to long-lasting responses.

Looking ahead, three key scientific questions will shape the next phase of progress. First, can drug repurposing strategies be systematically integrated with KRAS G12C inactive and active inhibitors to target complementary vulnerabilities and overcome resistance? Second, can rational combination therapies be optimised for specific molecular subgroups, such as STK11 or KEAP1 co-mutated tumours, to enable more effective precision medicine and improve long-term outcomes? Third, can advanced translational tools, including ctDNA monitoring and patient-derived models, be effectively used to guide real-time treatment decisions and optimise therapeutic sequencing?

The focus has now shifted from asking whether KRAS G12C is druggable to understanding how therapeutic responses can be made more effective, durable, and precisely matched to tumour biology. With continued integration of combination strategies, biomarker-driven approaches, and innovative clinical trial designs, the field is well-positioned to more closer to achieving sustained clinical benefit for patients with KRAS G12C-mutant NSCLC.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

The authors acknowledge the support and infrastructure offered by JSS Science and Technology University, Mysuru, India, JSS Academy of Higher Education and Research (JSS AHER), Mysuru, India, KVC Superspeciality Hospital, the Director, Amrita Vishwa Vidyapeetham, Mysuru campus, India and Instituto Oncológico Dr Rosell (IOR), Barcelona, Spain. The authors thank JSS AHER for financial support. The authors also acknowledge the Department of Biotechnology (DBT), Ministry of Science and Technology, for the Research Associate Fellowship.

Author contribution

Conception and design: A.J., R.R., B.S., A.P., C.S., M.N.N.P.; Collection and assembly of data: A.J., C.D., B.S., A.S.; Data analysis: A.J., R.R., M.G.C., C.D., C.S., M.N.N.P.; Manuscript writing: A.J., R.R., A.S.; Manuscript review and editing: All authors; Final approval of manuscript: All authors. The authors confirm that no paper mill and artificial intelligence was used.

Funding

Open access funding provided by JSS Academy of Higher Education and Research, Mysore. This work was supported by the Department of Biotechnology, Ministry of Science and Technology, in the form of Research Associate Fellowship.

Data availability

All source data for this work (or generated in this study) are available upon reasonable request.

Declarations

Ethical statement

Not applicable.

Competing interest

The authors declare no competing interests.

Clinical trial number

Not applicable.

Generative AI statement

Generative AI and AI-assisted technologies were not used in the preparation of this work.

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