Journal of experimental & clinical cancer research : CR · 2026
Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids.
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Choi Jin Ho, Lee Kyung Min, Oh Minsik, Noh Janghyun, Kim Yooyeon, Hwang Eunhye, Cho In Rae, Paik Woo Hyun, Ryu Ji Kon, Ku Ja-Lok, Lee Sang Hyub
Аннотация
BACKGROUND: Oxaliplatin resistance remains a significant challenge in pancreatic cancer (PC) treatment. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising therapeutic target for overcoming chemotherapy resistance. This study investigated whether ferroptosis induction could overcome oxaliplatin resistance in PC.
METHODS: We established 42 patient-derived pancreatic cancer organoids (PDPCOs) and performed comprehensive molecular profiling including whole-exome sequencing, RNA sequencing and drug response assays. Cell viability, lipid peroxidation, iron levels, mitochondrial function, and drug synergy were evaluated. Survival analysis and differential gene expression analyses were conducted according to the biomarker candidate.
RESULTS: Transcriptomic analysis revealed distinct ferroptosis-related alterations in OXA-resistant PDPCOs, including a negative enrichment of ferroptosis suppressor genes. The ferroptosis inducer artesunate (ART) synergistically enhanced anticancer effects of OXA in cell lines and PDPCOs. Mechanistic studies demonstrated that combination therapy induced ferroptotic cell death by promoting lipid peroxidation, intracellular iron accumulation, and mitochondrial dysfunction. Combination therapy remarkably inhibited tumor growth in PDPCO-derived xenograft models. ART/OXA treatment upregulated expressions of iron transport proteins transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1), contributing to ferroptosis induction. Overexpression of solute carrier family 7 member 11 (SLC7A11) conferred dual resistance to OXA and ART by suppressing ferroptosis, whereas its knockdown or pharmacological inhibition with erastin sensitized resistant cells to combination therapy. Notably, triple combination of ART, OXA, and erastin effectively overcame resistance in dual-resistant PDPCOs.
CONCLUSIONS: Ferroptosis-based therapeutic strategies can overcome oxaliplatin resistance in PC, supporting further investigation of SLC7A11 as a candidate biomarker for ferroptosis-based therapeutic responsiveness.
METHODS: We established 42 patient-derived pancreatic cancer organoids (PDPCOs) and performed comprehensive molecular profiling including whole-exome sequencing, RNA sequencing and drug response assays. Cell viability, lipid peroxidation, iron levels, mitochondrial function, and drug synergy were evaluated. Survival analysis and differential gene expression analyses were conducted according to the biomarker candidate.
RESULTS: Transcriptomic analysis revealed distinct ferroptosis-related alterations in OXA-resistant PDPCOs, including a negative enrichment of ferroptosis suppressor genes. The ferroptosis inducer artesunate (ART) synergistically enhanced anticancer effects of OXA in cell lines and PDPCOs. Mechanistic studies demonstrated that combination therapy induced ferroptotic cell death by promoting lipid peroxidation, intracellular iron accumulation, and mitochondrial dysfunction. Combination therapy remarkably inhibited tumor growth in PDPCO-derived xenograft models. ART/OXA treatment upregulated expressions of iron transport proteins transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1), contributing to ferroptosis induction. Overexpression of solute carrier family 7 member 11 (SLC7A11) conferred dual resistance to OXA and ART by suppressing ferroptosis, whereas its knockdown or pharmacological inhibition with erastin sensitized resistant cells to combination therapy. Notably, triple combination of ART, OXA, and erastin effectively overcame resistance in dual-resistant PDPCOs.
CONCLUSIONS: Ferroptosis-based therapeutic strategies can overcome oxaliplatin resistance in PC, supporting further investigation of SLC7A11 as a candidate biomarker for ferroptosis-based therapeutic responsiveness.