KRAS驱动的磷酸戊糖途径重塑赋予了一种可靶向的脆弱性，与MRTX1133协同作用，可使胰腺导管腺癌实现持久缓解。

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

作者信息

Jiang Xiangyan, Wang Tao, Zhao Bin, Sun Haonan, Dong Yuman, Ma Yong, Li Zhigang, Wu Yuxia, Wang Keshen, Guan Xiaoying, Long Bo, Qin Long, Shi Wengui, Shi Lei, He Qichen, Liu Wenbo, Li Mingdou, Xiao Lixia, Zhou Chengliang, Sun Hui, Yang Jing, Guan Junhong, Zhou Huinian, Yu Zeyuan, Jiao Zuoyi

机构信息

Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China; The Second Clinical Medical School, Lanzhou University, Lanzhou 730000, China.

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.

出版信息

Cell Rep Med. 2025 Feb 18;6(2):101966. doi: 10.1016/j.xcrm.2025.101966.

DOI:10.1016/j.xcrm.2025.101966

PMID:39970873

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11866490/

Abstract

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

摘要

KRAS抑制剂MRTX1133显示出革新胰腺导管腺癌（PDAC）治疗模式的潜力，但也带来了挑战。我们的研究结果表明，KRAS重塑了以磷酸戊糖途径（PPP）为主导的中心碳代谢模式，促进了PDAC的恶性进展和对MRTX1133的耐药性。从机制上讲，KRAS通过视网膜母细胞瘤（Rb）/E2F1/p53轴调节的反馈环驱动p53的过度降解和葡萄糖-6-磷酸脱氢酶（G6PD）介导的PPP重编程，该反馈环放大了泛素结合酶E2T（UBE2T）的转录。对UBE2T进行基因敲除或药物抑制可显著抑制PDAC进展并增强MRTX1133的疗效。利用UBE2T抑制剂五倍子酰葡萄糖（PGG）的结构优势，我们开发了一种由F-127、PGG和MRTX1133组成的自组装纳米共递送系统。该系统增强了PGG和MRTX1133的疗效，在患者来源的异种移植瘤和自发性PDAC小鼠中实现了持久缓解（总缓解率85%）和长期生存（无进展生存率100%）。本研究揭示了KRAS偏好的PPP重编程在MRTX1133耐药中的作用，并提出了一种针对KRAS突变型PDAC的潜在治疗策略。