ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC.

Autor: Tran NL; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA.; Cancer Molecular Therapeutics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA., Jiang J; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA., Ma M; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA., Gadbois GE; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA., Gulay KCM; Department of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA., Verano A; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02115., Zhou H; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA., Huang CT; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA., Scott DA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA., Bang AG; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA., Tiriac H; Department of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA., Lowy AM; Department of Surgery, Division of Surgical Oncology, UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA., Wang ES; Cancer Molecular Therapeutics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA., Ferguson FM; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 May 21. Date of Electronic Publication: 2024 May 21.
DOI: 10.1101/2024.05.19.594824
Abstrakt: Over 95% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic mutations in K-Ras. Upon treatment with K-Ras inhibitors, PDAC cancer cells undergo metabolic reprogramming towards an oxidative phosphorylation-dependent, drug-resistant state. However, direct inhibition of complex I is poorly tolerated in patients due to on-target induction of peripheral neuropathy. In this work, we develop molecular glue degraders against ZBTB11, a C 2 H 2 zinc finger transcription factor that regulates the nuclear transcription of components of the mitoribosome and electron transport chain. Our ZBTB11 degraders leverage the differences in demand for biogenesis of mitochondrial components between human neurons and rapidly-dividing pancreatic cancer cells, to selectively target the K-Ras inhibitor resistant state in PDAC. Combination treatment of both K-Ras inhibitor-resistant cell lines and multidrug resistant patient-derived organoids resulted in superior anti-cancer activity compared to single agent treatment, while sparing hiPSC-derived neurons. Proteomic and stable isotope tracing studies revealed mitoribosome depletion and impairment of the TCA cycle as key events that mediate this response. Together, this work validates ZBTB11 as a vulnerability in K-Ras inhibitor-resistant PDAC and provides a suite of molecular glue degrader tool compounds to investigate its function.
Competing Interests: CONFLICT OF INTEREST F.M.F., E.S.W., J.W.J. and N.L.T. are inventors on a patent application relating to this work (US 63/515,472). F.M.F. is a scientific co-founder and equity holder in Proximity Therapeutics, and was previously a scientific advisory board member (SAB) of Triana Biomedicines. F.M.F. is or was recently a consultant or received speaking honoraria from Eli Lilly and Co., RA Capital, Tocris BioTechne, and Plexium Inc. The Ferguson lab receives or has received research funding or resources in kind from Ono Pharmaceutical Co. Ltd, Eli Lilly and Co., and Merck and Co. F.M.F.’s interests have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies.
Databáze: MEDLINE
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