Dual Inhibition of KRAS G12D and PI3K/BRD4 signaling overcomes therapeutic resistance in pancreatic cancer.

Oncogenic KRAS G12D mutations drive pancreatic ductal adenocarcinoma (PDAC) but face therapeutic resistance from pathway reactivation. We synthesized MDP5, a dual BRD4/PI3K inhibitor, to address this issue. When combined with the KRAS G12D inhibitor MRTX1133, MDP5 resensitized resistant cancer cells. This combination synergistically enhanced apoptosis and proliferation inhibition, outperforming the standard-of-care, Gemcitabine (GEM). This dual-inhibition strategy effectively counters resistance mechanisms in KRAS-mutant PDAC, offering a promising therapeutic approach. We formulated MUC4-targeted polymeric nanoparticles co-loading MRTX1133 (8.3%) and MDP5 (7.4%) that exhibited pH-responsive release and uniform morphology. This targeted delivery translated to superior anti-tumor efficacy, as the combination of NPs markedly reduced tumor burden more effectively than single-drug treatments or a polymer-Gemcitabine conjugate. Importantly, this potent therapeutic effect was achieved without inducing detectable liver highlighting the potential, safe, and effective cancer therapy. Mechanistically, dual targeting reduced p-AKT and YAP1, depleted CD44+/ALDH+ cancer-stem-like cells, and reprogrammed the tumor immune microenvironment by elevating CD8a and CD86 while lowering Ly-6 G. Targeted co-delivery of MRTX1133 and MDP5 simultaneously inhibits the KRAS G12D and PI3K pathways. This dual-action approach aims to overcome therapeutic resistance, offering potentially more durable and precise treatment for patients with KRAS G12D-mutant pancreatic cancer. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is commonly driven by KRAS G12D, yet the KRAS G12D inhibitor MRTX1133 faces rapid adaptive resistance and delivery hurdles. We engineered MUC4-targeted polymer nanoparticles that co-deliver MRTX1133 with MDP5, a dual BRD4/PI3K blocker. The particles show uniform size, high loading, and pH-triggered release, increasing intratumoral drug levels versus free drugs. In orthotopic PDAC, the combination outperformed monotherapies and gemcitabine without overt toxicity. Mechanistically, dual inhibition suppresses AKT/YAP signaling, depletes CD44+/ALDH+ cells, and shifts the tumor immune milieu (↑CD8a, ↑CD86, ↓Ly-6 G). By integrating molecular targeting with multi-pathway blockade, this work addresses two major barriers-resistance and delivery-and outlines a generalizable strategy to improve precision nano therapy for KRAS-mutant pancreatic cancer.