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ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDAC
Nathan L Tran1,2, Jiewei Jiang1, Min Ma1
1Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA.
Abstract:
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 C2H2 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.
Insights
New molecular glues target ZBTB11 to overcome K-Ras inhibitor resistance in pancreatic cancer. This approach selectively depletes mitochondrial components in cancer cells, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) frequently harbors K-Ras mutations, leading to resistance upon K-Ras inhibitor treatment via metabolic reprogramming.
- Drug resistance in PDAC cells shifts metabolism towards oxidative phosphorylation, a state vulnerable to mitochondrial complex I inhibition, but this is poorly tolerated due to neurotoxicity.
Approach:
- Developed novel molecular glue degraders targeting ZBTB11, a transcription factor regulating mitochondrial ribosome and electron transport chain components.
- Leveraged differential demand for mitochondrial biogenesis between neurons and cancer cells to achieve selective targeting of resistant PDAC.
- Validated ZBTB11 degraders in combination therapy against K-Ras inhibitor-resistant cell lines and patient-derived organoids.
Key Points:
- ZBTB11 degraders demonstrated superior anti-cancer activity in combination treatments compared to single agents.
- Treatment spared human induced pluripotent stem cell-derived neurons, indicating a favorable safety profile.
- Proteomic and stable isotope tracing revealed mitoribosome depletion and TCA cycle impairment as key mechanisms of action.
Conclusions:
- ZBTB11 is a validated vulnerability in K-Ras inhibitor-resistant PDAC.
- Molecular glue degraders targeting ZBTB11 offer a selective therapeutic strategy for resistant pancreatic cancer.
- This work provides valuable tool compounds for further investigation of ZBTB11 function in cancer metabolism.
