Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins

Ryosuke Shirasaki, Geoffrey M. Matthews, Sara Gandolfi, Ricardo de Matos Simoes, Dennis L. Buckley, Joseline Raja Vora, Quinlan L. Sievers, Johanna B. Brüggenthies, Olga Dashevsky, Haley Poarch, Huihui Tang, Megan A. Bariteau, Michal Sheffer, Yiguo Hu, Sondra L. Downey-Kopyscinski, Paul J. Hengeveld, Brian J. Glassner, Eugen Dhimolea, Christopher J. Ott, Tinghu ZhangNicholas P. Kwiatkowski, Jacob P. Laubach, Robert L. Schlossman, Paul G. Richardson, Aedin C. Culhane, Richard W.J. Groen, Eric S. Fischer, Francisca Vazquez, Aviad Tsherniak, William C. Hahn, Joan Levy, Daniel Auclair, Jonathan D. Licht, Jonathan J. Keats, Lawrence H. Boise, Benjamin L. Ebert, James E. Bradner, Nathanael S. Gray, Constantine S. Mitsiades

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Genome-scale CRISPR gene editing studies by Shirasaki et al. reveal which genes confer myeloma cell resistance to PROTACs that leverage different E3 ligases to degrade various oncoproteins. The study provides a framework for sequential/alternating versus combined use of PROTACs, depending on which E3 ligase and oncoprotein they engage.

Original languageEnglish
Article number108532
JournalCell Reports
Volume34
Issue number1
DOIs
StatePublished - 5 Jan 2021
Externally publishedYes

Keywords

  • CRBN
  • CRISPR
  • CRISPR activation
  • E3 ligase
  • PROTAC
  • VHL
  • heterobifunctional proteolysis-targeting chimeric compounds
  • myeloma
  • pharmacological degraders
  • resistance

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