2. Academic Validation
  3. ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC

ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC

  • Nat Chem Biol. 2026 Feb;22(2):260-273. doi: 10.1038/s41589-025-01978-1.
Nathan L Tran # 1 2,  Jiewei Jiang # 1,  Min Ma 1,  Gillian E Gadbois 1,  Kevin C M Gulay 3,  Alyssa L Verano 4,  Cara R Schiavon 5,  Elena Rebollo 5 6,  Haowen Zhou 7,  Chun-Teng Huang 7,  Rabi Murad 7,  David A Scott 7,  Uri Manor 5,  Anne G Bang 3,  Herve Tiriac 3,  Andrew M Lowy 3,  Eric S Wang 8,  Fleur M Ferguson 9 10
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • 2 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 3 Department of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, USA.
  • 6 Molecular Biology Institute of Barcelona, Barcelona, Spain.
  • 7 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 8 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. [email protected].
  • 9 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. [email protected].
  • 10 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 40789946 DOI: 10.1038/s41589-025-01978-1
Abstract

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.

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