Tran Nathan L, Jiang Jiewei, Ma Min, Gadbois Gillian E, Gulay Kevin C M, Verano Alyssa L, Schiavon Cara R, Rebollo Elena, Zhou Haowen, Huang Chun-Teng, Murad Rabi, Scott David A, Manor Uri, Bang Anne G, Tiriac Herve, Lowy Andrew M, Wang Eric S, Ferguson Fleur M
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Nat Chem Biol. 2025 Aug 11. doi: 10.1038/s41589-025-01978-1.
Over 95% of pancreatic ductal adenocarcinomas (PDACs) harbor oncogenic mutations in KRAS. However, upon treatment with KRAS inhibitors, PDAC cells undergo rapid metabolic reprogramming toward an oxidative phosphorylation (OXPHOS)-dependent, drug-resistant state. Here, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11 and both the metabolic state and resistance to KRAS inhibitors can be attenuated by ZBTB11 depletion. We develop molecular glue degraders of ZBTB11 and demonstrate that they reprogram the aberrant transcriptome, proteome, metabolome and bioenergetics of KRAS inhibitor-resistant PDAC, resensitizing them to KRAS inhibition. ZBTB11 degradation leverages cell-type-specific and cell-state-specific differences in gene-regulatory mechanisms controlling OXPHOS pathway transcripts to selectively target the KRAS inhibitor-resistant state in PDAC while sparing neurons derived from human induced pluripotent stem cells. Together, this work establishes ZBTB11 as a druggable vulnerability in KRAS inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
超过95%的胰腺导管腺癌（PDAC）在KRAS基因中存在致癌突变。然而，在用KRAS抑制剂治疗后，PDAC细胞会迅速发生代谢重编程，转向依赖氧化磷酸化（OXPHOS）的耐药状态。在此，我们证明这种代谢转变与转录因子ZBTB11的上调有关，并且通过敲低ZBTB11，代谢状态和对KRAS抑制剂的耐药性均可被减弱。我们开发了ZBTB11的分子胶降解剂，并证明它们可重新编程KRAS抑制剂耐药PDAC的异常转录组、蛋白质组、代谢组和生物能量学，使其对KRAS抑制重新敏感。ZBTB11的降解利用了控制OXPHOS途径转录本的基因调控机制中细胞类型特异性和细胞状态特异性的差异，以选择性地靶向PDAC中KRAS抑制剂耐药状态，同时不影响源自人诱导多能干细胞的神经元。总之，这项工作确立了ZBTB11是KRAS抑制剂耐药PDAC中一个可成药的薄弱环节，并提供了一套分子胶降解剂工具化合物来研究其功能。
