KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC

Abstract

The KRAS G12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRAS G12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS G12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming through retinoblastoma (Rb)/E2F1/p53 axis-regulated feedback loops that amplify ubiquitin-conjugating enzyme E2T (UBE2T) transcription. Genetic ablation or pharmacological inhibition of UBE2T significantly suppresses PDAC progression and potentiates MRTX1133 efficacy. Leveraging structure advantages of the UBE2T inhibitor pentagalloylglucose (PGG), we develop a self-assembling nano co-delivery system with F-127, PGG, and MRTX1133. This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRAS G12D -preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRAS G12D -mutated PDAC. • KRAS G12D -driven PPP remodeling promotes PDAC progression and MRTX1133 resistance • KRAS G12D promotes PPP reprogramming via Rb/E2F1/UBE2T/p53 feedback loops • UBE2T confers progression and resistance to MRTX1133 in KRAS G12D -mutated PDAC • Nano co-delivery of the UBE2T inhibitor and MRTX1133 achieves durable remissions Jiang et al. uncover that KRAS G12D drives a pentose phosphate pathway-dominant reprogramming of central carbon metabolism through UBE2T-mediated feedback mechanisms. They develop a nano co-delivery system combining F-127, the UBE2T inhibitor PGG, and the KRAS G12D inhibitor MRTX1133, inducing significant tumor regression and durable therapeutic responses in KRAS G12D -mutant PDAC.