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Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.
Shirasaki, Ryosuke; Matthews, Geoffrey M; Gandolfi, Sara; de Matos Simoes, Ricardo; Buckley, Dennis L; Raja Vora, Joseline; Sievers, Quinlan L; Brüggenthies, Johanna B; Dashevsky, Olga; Poarch, Haley; Tang, Huihui; Bariteau, Megan A; Sheffer, Michal; Hu, Yiguo; Downey-Kopyscinski, Sondra L; Hengeveld, Paul J; Glassner, Brian J; Dhimolea, Eugen; Ott, Christopher J; Zhang, Tinghu; Kwiatkowski, Nicholas P; Laubach, Jacob P; Schlossman, Robert L; Richardson, Paul G; Culhane, Aedin C; Groen, Richard W J; Fischer, Eric S; Vazquez, Francisca; Tsherniak, Aviad; Hahn, William C; Levy, Joan; Auclair, Daniel; Licht, Jonathan D; Keats, Jonathan J; Boise, Lawrence H; Ebert, Benjamin L; Bradner, James E; Gray, Nathanael S; Mitsiades, Constantine S.
Afiliação
  • Shirasaki R; 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.
  • Matthews GM; 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.
  • Gandolfi S; 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.
  • de Matos Simoes R; 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.
  • Buckley DL; 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.
  • Raja Vora J; 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.
  • Sievers QL; 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.
  • Brüggenthies JB; 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.
  • Dashevsky O; 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.
  • Poarch H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Tang H; 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.
  • Bariteau MA; 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.
  • Sheffer M; 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.
  • Hu Y; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Downey-Kopyscinski SL; 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.
  • Hengeveld PJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Glassner BJ; 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.
  • Dhimolea E; 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.
  • Ott CJ; 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.
  • Zhang T; Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Kwiatkowski NP; Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Laubach JP; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Schlossman RL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Richardson PG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • Culhane AC; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Groen RWJ; Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands.
  • Fischer ES; Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Vazquez F; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tsherniak A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hahn WC; 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.
  • Levy J; Multiple Myeloma Research Foundation, Norwalk, CT, USA.
  • Auclair D; Multiple Myeloma Research Foundation, Norwalk, CT, USA.
  • Licht JD; University of Florida Health Cancer Center, Gainesville, FL, USA.
  • Keats JJ; Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Boise LH; Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • Ebert BL; 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.
  • Bradner JE; 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.
  • Gray NS; Harvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Mitsiades CS; 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: constantine_mitsiades@dfci.harvard.edu.
Cell Rep ; 34(1): 108532, 2021 01 05.
Article em En | MEDLINE | ID: mdl-33406420
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ubiquitina-Proteína Ligases / Proteínas Adaptadoras de Transdução de Sinal / Proteína Supressora de Tumor Von Hippel-Lindau / Mieloma Múltiplo / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ubiquitina-Proteína Ligases / Proteínas Adaptadoras de Transdução de Sinal / Proteína Supressora de Tumor Von Hippel-Lindau / Mieloma Múltiplo / Antineoplásicos Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos