KRAS<sup>G12D</sup>-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39970873.
- Also identified by DOI 10.1016/j.xcrm.2025.101966 and PMC identifier 11866490.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The KRAS<sup>G12D</sup> inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRAS<sup>G12D</sup> remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRAS<sup>G12D</sup> 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<sup>G12D</sup>-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRAS<sup>G12D</sup>-mutated PDAC.
Medical subject headings
- Pentose Phosphate Pathway
- Pancreatic Neoplasms
- Carcinoma, Pancreatic Ductal
- Proto-Oncogene Proteins p21(ras)