KRAS^G12D-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. Leveragi

SUBMITTER: Jiang X 

PROVIDER: S-EPMC11866490 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature