Journal
CELL REPORTS
Volume 34, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108532
Keywords
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Categories
Funding
- NIH [R01 CA050947, CA179483, CA196664, CA180475, U01 CA225730, U01CA176058]
- de Gunzburg Myeloma Research Fund
- Ludwig Center at Harvard
- International Myeloma Foundation
- Lauri Strauss Leukemia Foundation
- Leukemia and Lymphoma Society (LLS) Scholar Award
- LLS Translational Research Program
- LLS Quest for Cure Program
- Multiple Myeloma Research Foundation (MMRF) Answer Fund
- MMRF Translational Network of Excellence
- MMRF Epigenetics Program
- Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research
- Cobb Family Myeloma Research Fund
- Chambers Family Advanced Myeloma Research Fund
- Department of Defense [W81XWH-15-1-0012, W81XWH-15-1-0013]
- American-Australian Association
- Associazione Italiana per la Ricerca sul Cancro
- Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute
- Damon Runyon Cancer Research Foundation [DRG219614]
- National Institute of General Medical Sciences [T32GM007753]
- MD Anderson Cancer Center support grant [5 P30 CA016672-40]
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The resistance mechanisms to degraders targeting different oncoproteins are mainly due to prevention, rather than adaptation, of the breakdown of target oncoproteins, which is possibly caused by the loss of function of the cognate E3 ligase or its interactors/regulators.
Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological degraders'' of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN-versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.
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