Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
Justin Cidado
Bioscience Oncology, IMED Biotech Unit, AstraZeneca, Waltham, United States
Bioscience Oncology, IMED Biotech Unit, AstraZeneca, Waltham, United States
Cortni Dick
Bioscience Oncology, IMED Biotech Unit, AstraZeneca, Waltham, United States
Pei-Chun Lin
Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Therese Mitros
Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Hong Ma
Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Seung Hyun Baik
Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Matthew A Belmonte
Bioscience Oncology, IMED Biotech Unit, AstraZeneca, Waltham, United States
Lisa Drew
Bioscience Oncology, IMED Biotech Unit, AstraZeneca, Waltham, United States
Innovative Genomics Institute, University of California, Berkeley, Berkeley, United States; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
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 anticancer agents suggests the potential to improve combination treatments.
