ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC

Nathan L Tran^#^{1

2}, Jiewei Jiang^#¹, Min Ma¹, Gillian E Gadbois¹, Kevin C M Gulay³, Alyssa L Verano⁴, Cara R Schiavon⁵, Elena Rebollo^{5

6}, Haowen Zhou⁷, Chun-Teng Huang⁷, Rabi Murad⁷, David A Scott⁷, Uri Manor⁵, Anne G Bang³, Herve Tiriac³, Andrew M Lowy³, Eric S Wang⁸, Fleur M Ferguson^{9

10}

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. ewang@sbpdiscovery.org.
⁹ Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. fmferguson@ucsd.edu.
¹⁰ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA. fmferguson@ucsd.edu.

^# Contributed equally.

PMID: 40789946
DOI: 10.1038/s41589-025-01978-1

ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC

Nathan L Tran et al. Nat Chem Biol. 2025.

. 2025 Aug 11.

doi: 10.1038/s41589-025-01978-1. Online ahead of print.

Authors

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. ewang@sbpdiscovery.org.
⁹ Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA. fmferguson@ucsd.edu.
¹⁰ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA. fmferguson@ucsd.edu.

^# 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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Conflict of interest statement

Competing interests: F.M.F., E.S.W., J.J. and N.L.T. are inventors on a patent application related to this work (US 63/515,472). The E.S.W. lab receives or has received research resources in kind from SK Life Sciences. F.M.F. is a scientific cofounder and equity holder in Proximity Therapeutics and was previously a scientific advisory board member of Triana Biomedicines. F.M.F. is or was recently a consultant or received speaking honoraria from RA Capital, Tocris BioTechne, Eli Lilly, Amgen, Neomorph and Plexium. The F.M.F. lab receives or has received research funding, travel funding or resources in kind from Ono Pharmaceutical, Eli Lilly, Promega and Merck. F.M.F.’s interests have been reviewed and approved by UCSD in accordance with its conflict-of-interest policies. The remaining authors declare no competing interests.

Update of

ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC.
Tran NL, Jiang J, Ma M, Gadbois GE, Gulay KCM, Verano A, Zhou H, Huang CT, Scott DA, Bang AG, Tiriac H, Lowy AM, Wang ES, Ferguson FM. Tran NL, et al. bioRxiv [Preprint]. 2024 May 21:2024.05.19.594824. doi: 10.1101/2024.05.19.594824. bioRxiv. 2024. Update in: Nat Chem Biol. 2025 Aug 11. doi: 10.1038/s41589-025-01978-1. PMID: 38826238 Free PMC article. Updated. Preprint.

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ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC

Affiliations

ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References