KRASG12D-driven pentose phosphate pathway remodeling imparts a targetable vulnerability synergizing with MRTX1133 for durable remissions in PDAC
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.
Authors
- Chenhe Zhou (ORCID: https://orcid.org/0000-0002-5471-1022)
- Hongyu Sun (ORCID: https://orcid.org/0000-0002-5926-4495)
- Junhong Guan (ORCID: https://orcid.org/0000-0003-4900-0610)
- Bo Long (ORCID: https://orcid.org/0000-0002-9358-2585)
- Yuman Dong (ORCID: https://orcid.org/0000-0003-2342-5338)
- Huinian Zhou (ORCID: https://orcid.org/0000-0003-0727-463X)
- Wenbo Liu (ORCID: https://orcid.org/0000-0003-0445-2357)
- Zhigang Li (ORCID: https://orcid.org/0000-0001-5086-5334)
- Bin Zhao (ORCID: https://orcid.org/0000-0001-6477-1769)
- Mingdou Li
- Xiangyan Jiang (ORCID: https://orcid.org/0000-0002-2685-2899)
- Long Qin (ORCID: https://orcid.org/0000-0003-1427-1672)
- Zuoyi Jiao (ORCID: https://orcid.org/0000-0003-1942-0905)
- Qichen He (ORCID: https://orcid.org/0009-0006-3187-7130)
- Keshen Wang (ORCID: https://orcid.org/0000-0001-5526-2129)
- Tao Wang (ORCID: https://orcid.org/0000-0002-4355-149X)
- Jing Yang (ORCID: https://orcid.org/0000-0003-0164-9699)
- Lei Shi (ORCID: https://orcid.org/0000-0002-6043-8819)
- Wengui Shi
- Lixia Xiao (ORCID: https://orcid.org/0000-0002-8894-8677)
- Xiaoying Guan (ORCID: https://orcid.org/0000-0002-6544-8143)
- Yuxia Wu (ORCID: https://orcid.org/0000-0003-3001-5783)
- Yong Ma
- Haonan Sun (ORCID: https://orcid.org/0009-0006-3933-7171)
- Zeyuan Yu (ORCID: https://orcid.org/0000-0002-7814-5416)
Institutions
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- Lanzhou University Second Hospital (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101966
- Citations
- 10
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Gansu Province
- Lanzhou Science and Technology Bureau
- Science and Technology Department of Gansu Province
- Fundamental Research Funds for the Central Universities