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ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC
Nathan L Tran1,2, Jiewei Jiang1, Min Ma1
1Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
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.
Insights
Pancreatic cancer cells become resistant to KRAS inhibitors by altering metabolism. Targeting the transcription factor ZBTB11 with molecular glues resensitizes these cells to treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Pancreatic ductal adenocarcinoma (PDAC) frequently harbors KRAS mutations.
- KRAS inhibitors induce metabolic reprogramming in PDAC, leading to drug resistance.
- This resistance is linked to oxidative phosphorylation (OXPHOS)-dependent states.
Purpose of the Study:
- To investigate the role of transcription factor ZBTB11 in KRAS inhibitor resistance in PDAC.
- To develop novel therapeutic strategies targeting ZBTB11 to overcome drug resistance.
- To explore ZBTB11 as a druggable vulnerability in PDAC.
Main Methods:
- Investigated the association between ZBTB11 upregulation and metabolic reprogramming in KRAS inhibitor-resistant PDAC.
- Developed molecular glue degraders targeting ZBTB11.
- Assessed the effects of ZBTB11 depletion and degradation on PDAC transcriptome, proteome, metabolome, and bioenergetics.
- Evaluated the resensitization of PDAC to KRAS inhibition upon ZBTB11 degradation.
- Examined the cell-type specificity of ZBTB11 degradation in PDAC versus human neurons.
Main Results:
- ZBTB11 upregulation correlates with the OXPHOS-dependent, drug-resistant state in PDAC.
- Depletion of ZBTB11 attenuates the drug-resistant metabolic state and restores sensitivity to KRAS inhibitors.
- Developed molecular glue degraders of ZBTB11 effectively reprogram PDAC.
- ZBTB11 degradation resensitizes KRAS inhibitor-resistant PDAC to KRAS inhibition.
- Selective targeting of ZBTB11 degradation in PDAC spares neurons.
Conclusions:
- ZBTB11 is a key mediator of metabolic reprogramming and drug resistance in PDAC.
- ZBTB11 represents a druggable vulnerability in KRAS inhibitor-resistant PDAC.
- Molecular glue degraders of ZBTB11 offer a promising therapeutic strategy for overcoming resistance in PDAC.
