The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells
- University of California, Berkeley, United States
- AstraZeneca, United States
Abstract
Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL are frequently observed in many cancers. Inhibitors targeting MCL1 are in clinical development, however numerous cancer models are intrinsically resistant to this approach. To discover mechanisms underlying resistance to MCL1 inhibition, we performed multiple flow-cytometry based genome-wide CRISPR screens interrogating two drugs that directly (MCL1i) or indirectly (CDK9i) target MCL1. Remarkably, both screens identified three components (CUL5, RNF7 and UBE2F) of a cullin-RING ubiquitin ligase complex (CRL5) that resensitized cells to MCL1 inhibition. We find that levels of the BH3-only pro-apoptotic proteins Bim and Noxa are proteasomally regulated by the CRL5 complex. Accumulation of Noxa caused by depletion of CRL5 components was responsible for re-sensitization to CDK9 inhibitor, but not MCL1 inhibitor. Discovery of a novel role of CRL5 in apoptosis and resistance to multiple types of anti-cancer agents suggests the potential to improve combination treatments.
Data availability
Sequencing data is being deposited into SRA under accession code: SUB5033643
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Genome-wide CRISPRi Resensitization Screens with MCL1 InhibitorsNCBI Sequence Read Archive, SUB5033643.
Article and author information
Author details
Funding
AstraZeneca
- Shaheen Kabir
- Justin Cidado
- Courtney Andersen
- Cortni Dick
- Pei-Chun Lin
- Hong Ma
- Matthew A Belmonte
- Lisa Drew
- Jacob E Corn
National Institutes of Health (DP2 HL141006)
- Jacob E Corn
Li Ka Shing Foundation
- Jacob E Corn
Heritage Medical Research Institute
- Jacob E Corn
California Institute for Regenerative Medicine (DISC1-08776)
- Shaheen Kabir
- Seung Hyun Baik
- Jacob E Corn
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Kabir et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells
eLife 8:e44288.
https://doi.org/10.7554/eLife.44288
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