ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC [Degrader RNA-seq]

Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. However, upon treatment with K-Ras inhibitors, PDAC cancer cells undergo rapid metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. In this work, we demonstrate that this metabolic shift is associated with upregulation of the transcription factor ZBTB11, and both the metabolic state and the K-Ras inhibitor drug resistance 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 K-Ras inhibitor resistant PDAC, resensitizing them to K-Ras inhibition. ZBTB11 degradation leverages cell-type and cell-state specific differences in gene regulatory mechanisms controlling OXPHOS-pathway transcripts to selectively target the K-Ras inhibitor resistant state in PDAC while sparing hiPSC-derived neurons. Together, this work establishes ZBTB11 as a druggable vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.