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

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

  • Cell Rep. 2021 Jan 5;34(1):108532. doi: 10.1016/j.celrep.2020.108532.
Ryosuke Shirasaki 1,  Geoffrey M Matthews 2,  Sara Gandolfi 1,  Ricardo de Matos Simoes 1,  Dennis L Buckley 2,  Joseline Raja Vora 2,  Quinlan L Sievers 2,  Johanna B Brüggenthies 2,  Olga Dashevsky 1,  Haley Poarch 3,  Huihui Tang 1,  Megan A Bariteau 2,  Michal Sheffer 1,  Yiguo Hu 4,  Sondra L Downey-Kopyscinski 2,  Paul J Hengeveld 4,  Brian J Glassner 1,  Eugen Dhimolea 1,  Christopher J Ott 5,  Tinghu Zhang 6,  Nicholas P Kwiatkowski 6,  Jacob P Laubach 4,  Robert L Schlossman 4,  Paul G Richardson 4,  Aedin C Culhane 7,  Richard W J Groen 8,  Eric S Fischer 6,  Francisca Vazquez 9,  Aviad Tsherniak 9,  William C Hahn 2,  Joan Levy 10,  Daniel Auclair 10,  Jonathan D Licht 11,  Jonathan J Keats 12,  Lawrence H Boise 13,  Benjamin L Ebert 2,  James E Bradner 2,  Nathanael S Gray 6,  Constantine S Mitsiades 14
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 8 Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands.
  • 9 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 10 Multiple Myeloma Research Foundation, Norwalk, CT, USA.
  • 11 University of Florida Health Cancer Center, Gainesville, FL, USA.
  • 12 Translational Genomics Research Institute, Phoenix, AZ, USA.
  • 13 Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 14 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: [email protected].
PMID: 33406420 DOI: 10.1016/j.celrep.2020.108532
Abstract

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.

Keywords

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

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