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

  • Cell Rep Med. 2025 Feb 18;6(2):101966. doi: 10.1016/j.xcrm.2025.101966.
Xiangyan Jiang  1 ,  Tao Wang  1 ,  Bin Zhao  1 ,  Haonan Sun  1 ,  Yuman Dong  2 ,  Yong Ma  1 ,  Zhigang Li  3 ,  Yuxia Wu  3 ,  Keshen Wang  1 ,  Xiaoying Guan  4 ,  Bo Long  5 ,  Long Qin  6 ,  Wengui Shi  6 ,  Lei Shi  7 ,  Qichen He  1 ,  Wenbo Liu  3 ,  Mingdou Li  3 ,  Lixia Xiao  1 ,  Chengliang Zhou  8 ,  Hui Sun  9 ,  Jing Yang  9 ,  Junhong Guan  9 ,  Huinian Zhou  5 ,  Zeyuan Yu  10 ,  Zuoyi Jiao  11
Affiliations
  • 1. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China.
  • 2. Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
  • 3. The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China.
  • 4. Department of Pathology, Lanzhou University Second Hospital, Lanzhou 730000, China.
  • 5. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China.
  • 6. Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China; Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China.
  • 7. School of Public Health, Lanzhou University, Lanzhou 730000, China.
  • 8. Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 9. Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou 730000, China.
  • 10. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China.
  • 11. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; Gansu Province High-Altitude High-Incidence Cancer Biobank, Lanzhou University Second Hospital, Lanzhou 730000, China. Electronic address: [email protected].
PMID: 39970873 DOI: 10.1016/j.xcrm.2025.101966
Abstract

The KRASG12D inhibitor MRTX1133 shows the potential to revolutionize the treatment paradigm for pancreatic ductal adenocarcinoma (PDAC), yet presents challenges. Our findings indicate that KRASG12D remodels a pentose phosphate pathway (PPP)-dominant central carbon metabolism pattern, facilitating malignant progression and resistance to MRTX1133 in PDAC. Mechanistically, KRASG12D 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 KRASG12D-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRASG12D-mutated PDAC.

Keywords
KRAS(G12D); MRTX1133; metabolic reprogramming; pancreatic ductal adenocarcinoma; pentose phosphate pathway.
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