KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC
The KRASG12D inhibitor MRTX1133 has potential for pancreatic ductal adenocarcinoma (PDAC) treatment, but challenges remain. This study found that KRASG12D remodels central carbon metabolism towards a pentose phosphate pathway (PPP)-dominant pattern, promoting PDAC progression and MRTX1133 resistance.
Mechanistically, KRASG12D drives excessive degradation of p53 and glucose-6-phosphate dehydrogenase (G6PD)-mediated PPP reprogramming. This occurs 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 enhances MRTX1133 efficacy. Using the UBE2T inhibitor pentagalloylglucose (PGG), a nano co-delivery system was developed with F-127, PGG, and MRTX1133.
This system enhanced the efficacy of PGG and MRTX1133, achieving durable remissions and long-term survival in patient-derived xenografts and spontaneous PDAC mice. This study reveals KRASG12D-preferred PPP reprogramming’s role in MRTX1133 resistance.
The study also proposes a potential therapeutic strategy for KRASG12D-mutated PDAC by targeting the UBE2T pathway.