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 Zhang; Nicholas 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

doi:https://doi.org/10.1016/j.celrep.2020.108532

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 journal › Article › Academic › peer-review

33 Citations (Scopus)

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 language	English
Article number	108532
Journal	Cell reports
Volume	34
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2020.108532
Publication status	Published - 5 Jan 2021

Keywords

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

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https://doi.org/10.1016/j.celrep.2020.108532

Cite this

Shirasaki, R., Matthews, G. M., Gandolfi, S., de Matos Simoes, R., Buckley, D. L., Raja Vora, J., Sievers, Q. L., Brüggenthies, J. B., Dashevsky, O., Poarch, H., Tang, H., Bariteau, M. A., Sheffer, M., Hu, Y., Downey-Kopyscinski, S. L., Hengeveld, P. J., Glassner, B. J., Dhimolea, E., Ott, C. J., ... Mitsiades, C. S. (2021). Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins. Cell reports, 34(1), [108532]. https://doi.org/10.1016/j.celrep.2020.108532

@article{9122b15667654023ab239fb2d654782d,

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

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.",

keywords = "CRBN, CRISPR, CRISPR activation, E3 ligase, PROTAC, VHL, heterobifunctional proteolysis-targeting chimeric compounds, myeloma, pharmacological degraders, resistance",

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

note = "Funding Information: The authors would like to thank William G. Kaelin (DFCI) and Cory Johannessen (Broad Institute) for insightful scientific comments on this work and Jeffrey D. Sorrell (DFCI) for his contribution to the organizational planning for this study. This work was supported by grants NIH R01 CA050947 (to C.S.M.), CA179483 (to C.S.M. and N.S.G.), CA196664 (to C.S.M. and R.W.J.G.), CA180475 (to J.D.L. and C.S.M.), and U01 CA225730 (to C.S.M.) , and U01CA176058 (to W.C.H.) and by the de Gunzburg Myeloma Research Fund (to C.S.M. and P.G.R.), the Ludwig Center at Harvard (to C.S.M.), the International Myeloma Foundation (to R.S. and G.M.M.), the Lauri Strauss Leukemia Foundation (to R.S.), a Leukemia and Lymphoma Society (LLS) Scholar Award (to C.S.M.), the LLS Translational Research Program (to C.S.M. and R.W.J.G.), the LLS Quest for Cure Program (to C.S.M. and R.W.J.G.), the Multiple Myeloma Research Foundation (MMRF) Answer Fund (to C.S.M., J.D.L., and L.H.B.), the MMRF Translational Network of Excellence (to C.S.M.), an MMRF Epigenetics Program Project grant (to J.D.L. and C.S.M.), the Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (to C.S.M.), the Cobb Family Myeloma Research Fund (to C.S.M.), the Chambers Family Advanced Myeloma Research Fund (to C.S.M. and P.G.R.), Department of Defense grants W81XWH-15-1-0012 (to C.S.M.) and W81XWH-15-1-0013 (to A.C.C.), the American-Australian Association (to G.M.M), Associazione Italiana per la Ricerca sul Cancro (to S.G.), and the Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute (to M.S., E.D., and C.S.M.). D.L.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation ( DRG219614 ). Q.L.S. was supported by award T32GM007753 from the National Institute of General Medical Sciences . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. RPPA analyses were conducted by the Functional Proteomics RPPA Core facility, which is supported by MD Anderson Cancer Center support grant 5 P30 CA016672-40 . Funding Information: The authors would like to thank William G. Kaelin (DFCI) and Cory Johannessen (Broad Institute) for insightful scientific comments on this work and Jeffrey D. Sorrell (DFCI) for his contribution to the organizational planning for this study. This work was supported by grants NIH R01 CA050947 (to C.S.M.), CA179483 (to C.S.M. and N.S.G.), CA196664 (to C.S.M. and R.W.J.G.), CA180475 (to J.D.L. and C.S.M.), and U01 CA225730 (to C.S.M.), and U01CA176058 (to W.C.H.) and by the de Gunzburg Myeloma Research Fund (to C.S.M. and P.G.R.), the Ludwig Center at Harvard (to C.S.M.), the International Myeloma Foundation (to R.S. and G.M.M.), the Lauri Strauss Leukemia Foundation (to R.S.), a Leukemia and Lymphoma Society (LLS) Scholar Award (to C.S.M.), the LLS Translational Research Program (to C.S.M. and R.W.J.G.), the LLS Quest for Cure Program (to C.S.M. and R.W.J.G.), the Multiple Myeloma Research Foundation (MMRF) Answer Fund (to C.S.M. J.D.L. and L.H.B.), the MMRF Translational Network of Excellence (to C.S.M.), an MMRF Epigenetics Program Project grant (to J.D.L. and C.S.M.), the Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (to C.S.M.), the Cobb Family Myeloma Research Fund (to C.S.M.), the Chambers Family Advanced Myeloma Research Fund (to C.S.M. and P.G.R.), Department of Defense grants W81XWH-15-1-0012 (to C.S.M.) and W81XWH-15-1-0013 (to A.C.C.), the American-Australian Association (to G.M.M), Associazione Italiana per la Ricerca sul Cancro (to S.G.), and the Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute (to M.S. E.D. and C.S.M.). D.L.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG219614). Q.L.S. was supported by award T32GM007753 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. RPPA analyses were conducted by the Functional Proteomics RPPA Core facility, which is supported by MD Anderson Cancer Center support grant 5 P30 CA016672-40. R.S. G.M.M. S.G. J.R.V. J.B.B. O.D. H.P. H.T. M.A.B. M.S. Y.H. S.L.D-K. P.J.H. B.J.G. and E.D. performed experiments or assisted with generation of experimental data. R.d.M.S. P.J.H. A.C.C. F.V. and A.T performed computational analyses, wrote and implemented software for data analysis and visualization, and/or provided interpretation of results from CRISPR screens for treatment resistance or essentiality. D.L.B. Q.L.S. Y.H. T.Z. N.P.K. B.L.E. J.E.B. and N.S.G. provided preclinical reagents. J.P.L. R.L.S. and P.G.R. provided clinical samples. D.A. and J.L. provided, on behalf of the MMRF CoMMpass study, data on myeloma patient-derived samples, and these data were analyzed by R.d.M.S. D.A. J.L. J.D.L. L.H.B. and J.J.K. J.D.L. L.H.B. J.J.K. R.W.J.G. C.J.O, E.S.F. F.V. A.T. W.C.H. J.E.B. and N.S.G, provided advisory or supervisory roles in various components of the experimental procedures, computational analyses, and data interpretation. C.S.M. conceived and supervised the study, which was designed by R.S. G.M.M. R.d.M.S. and C.S.M. R.S. G.M.M. S.G. R.d.M.S. J.D.L. and C.S.M. wrote and/or revised the manuscript with assistance from the other authors. F.V. receives research funding from Novo Ventures. P.G.R. reports research support from Oncopeptides, Celgene/BMS, and Takeda and is an advisory committee member for Karyopharm, Oncopeptides, Celgene/BMS, Takeda, Janssen, Sanofi, Secura Bio, and GSK. E.S.F. is a founder, science advisory board member, and equity holder in Civetta, Jengu (board member), and Neomorph; an equity holder in C4; and a consultant to Astellas, Novartis, Deerfield, and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, Ajax, and Deerfield. N.P.K. is a consultant to Epiphanes, Inc. W.C.H. is a consultant for Thermo Fisher, Solvasta, MPM Capital, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicines, RAPPTA Therapeutics, and Parexel and is a founder of and advisor to KSQ Therapeutics. L.H.B. receives research funding from AstraZeneca and is a consultant for AstraZeneca and Genentech. B.L.E. has received research funding from Celgene and Deerfield. He has received consulting fees from GRAIL, and he serves on the scientific advisory boards for and holds equity in Skyhawk Therapeutics and Exo Therapeutics. J.E.B. is an author on United States patent applications licensed from the Dana-Farber Cancer Institute to C4 Therapeutics (TPD) and Tensha Therapeutics (now Roche; BRD4 inhibition). He is now an executive of and shareholder in Novartis AG. N.S.G. is a scientific founder, member of the scientific advisory board and equity holder in C4 Therapeutics, Syros Pharmaceuticals, Petra Pharmaceuticals, Ravenna, Inception, Allorion, Jengu, and Soltego (board member) and is the inventor on intellectual property licensed to these entities. R.S. G.M.M. S.G. R.d.M.S. and C.S.M. are authors on a patent application on the use of degraders. C.S.M. also discloses consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals and FIMECS; employment of a relative with Takeda; and research funding from Janssen/Johnson & Johnson, TEVA, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix. Funding Information: F.V. receives research funding from Novo Ventures. P.G.R. reports research support from Oncopeptides, Celgene/BMS, and Takeda and is an advisory committee member for Karyopharm, Oncopeptides, Celgene/BMS, Takeda, Janssen, Sanofi, Secura Bio, and GSK. E.S.F. is a founder, science advisory board member, and equity holder in Civetta, Jengu (board member), and Neomorph; an equity holder in C4; and a consultant to Astellas, Novartis, Deerfield, and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, Ajax, and Deerfield. N.P.K. is a consultant to Epiphanes, Inc. W.C.H. is a consultant for Thermo Fisher, Solvasta, MPM Capital, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicines, RAPPTA Therapeutics, and Parexel and is a founder of and advisor to KSQ Therapeutics. L.H.B. receives research funding from AstraZeneca and is a consultant for AstraZeneca and Genentech. B.L.E. has received research funding from Celgene and Deerfield. He has received consulting fees from GRAIL, and he serves on the scientific advisory boards for and holds equity in Skyhawk Therapeutics and Exo Therapeutics. J.E.B. is an author on United States patent applications licensed from the Dana-Farber Cancer Institute to C4 Therapeutics (TPD) and Tensha Therapeutics (now Roche; BRD4 inhibition). He is now an executive of and shareholder in Novartis AG. N.S.G. is a scientific founder, member of the scientific advisory board and equity holder in C4 Therapeutics, Syros Pharmaceuticals, Petra Pharmaceuticals, Ravenna, Inception, Allorion, Jengu, and Soltego (board member) and is the inventor on intellectual property licensed to these entities. R.S., G.M.M., S.G., R.d.M.S., and C.S.M. are authors on a patent application on the use of degraders. C.S.M. also discloses consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals and FIMECS; employment of a relative with Takeda; and research funding from Janssen/Johnson & Johnson, TEVA, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix. Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jan,

day = "5",

doi = "https://doi.org/10.1016/j.celrep.2020.108532",

language = "English",

volume = "34",

journal = "Cell Reports",

issn = "2211-1247",

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Shirasaki, R, Matthews, GM, Gandolfi, S, de Matos Simoes, R, Buckley, DL, Raja Vora, J, Sievers, QL, Brüggenthies, JB, Dashevsky, O, Poarch, H, Tang, H, Bariteau, MA, Sheffer, M, Hu, Y, Downey-Kopyscinski, SL, Hengeveld, PJ, Glassner, BJ, Dhimolea, E, Ott, CJ, Zhang, T, Kwiatkowski, NP, Laubach, JP, Schlossman, RL, Richardson, PG, Culhane, AC, Groen, RWJ, Fischer, ES, Vazquez, F, Tsherniak, A, Hahn, WC, Levy, J, Auclair, D, Licht, JD, Keats, JJ, Boise, LH, Ebert, BL, Bradner, JE, Gray, NS & Mitsiades, CS 2021, 'Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins', Cell reports, vol. 34, no. 1, 108532. https://doi.org/10.1016/j.celrep.2020.108532

TY - JOUR

T1 - Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins

AU - Shirasaki, Ryosuke

AU - Matthews, Geoffrey M.

AU - Gandolfi, Sara

AU - de Matos Simoes, Ricardo

AU - Buckley, Dennis L.

AU - Raja Vora, Joseline

AU - Sievers, Quinlan L.

AU - Brüggenthies, Johanna B.

AU - Dashevsky, Olga

AU - Poarch, Haley

AU - Tang, Huihui

AU - Bariteau, Megan A.

AU - Sheffer, Michal

AU - Hu, Yiguo

AU - Downey-Kopyscinski, Sondra L.

AU - Hengeveld, Paul J.

AU - Glassner, Brian J.

AU - Dhimolea, Eugen

AU - Ott, Christopher J.

AU - Zhang, Tinghu

AU - Kwiatkowski, Nicholas P.

AU - Laubach, Jacob P.

AU - Schlossman, Robert L.

AU - Richardson, Paul G.

AU - Culhane, Aedin C.

AU - Groen, Richard W. J.

AU - Fischer, Eric S.

AU - Vazquez, Francisca

AU - Tsherniak, Aviad

AU - Hahn, William C.

AU - Levy, Joan

AU - Auclair, Daniel

AU - Licht, Jonathan D.

AU - Keats, Jonathan J.

AU - Boise, Lawrence H.

AU - Ebert, Benjamin L.

AU - Bradner, James E.

AU - Gray, Nathanael S.

AU - Mitsiades, Constantine S.

N1 - Funding Information: The authors would like to thank William G. Kaelin (DFCI) and Cory Johannessen (Broad Institute) for insightful scientific comments on this work and Jeffrey D. Sorrell (DFCI) for his contribution to the organizational planning for this study. This work was supported by grants NIH R01 CA050947 (to C.S.M.), CA179483 (to C.S.M. and N.S.G.), CA196664 (to C.S.M. and R.W.J.G.), CA180475 (to J.D.L. and C.S.M.), and U01 CA225730 (to C.S.M.) , and U01CA176058 (to W.C.H.) and by the de Gunzburg Myeloma Research Fund (to C.S.M. and P.G.R.), the Ludwig Center at Harvard (to C.S.M.), the International Myeloma Foundation (to R.S. and G.M.M.), the Lauri Strauss Leukemia Foundation (to R.S.), a Leukemia and Lymphoma Society (LLS) Scholar Award (to C.S.M.), the LLS Translational Research Program (to C.S.M. and R.W.J.G.), the LLS Quest for Cure Program (to C.S.M. and R.W.J.G.), the Multiple Myeloma Research Foundation (MMRF) Answer Fund (to C.S.M., J.D.L., and L.H.B.), the MMRF Translational Network of Excellence (to C.S.M.), an MMRF Epigenetics Program Project grant (to J.D.L. and C.S.M.), the Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (to C.S.M.), the Cobb Family Myeloma Research Fund (to C.S.M.), the Chambers Family Advanced Myeloma Research Fund (to C.S.M. and P.G.R.), Department of Defense grants W81XWH-15-1-0012 (to C.S.M.) and W81XWH-15-1-0013 (to A.C.C.), the American-Australian Association (to G.M.M), Associazione Italiana per la Ricerca sul Cancro (to S.G.), and the Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute (to M.S., E.D., and C.S.M.). D.L.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation ( DRG219614 ). Q.L.S. was supported by award T32GM007753 from the National Institute of General Medical Sciences . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. RPPA analyses were conducted by the Functional Proteomics RPPA Core facility, which is supported by MD Anderson Cancer Center support grant 5 P30 CA016672-40 . Funding Information: The authors would like to thank William G. Kaelin (DFCI) and Cory Johannessen (Broad Institute) for insightful scientific comments on this work and Jeffrey D. Sorrell (DFCI) for his contribution to the organizational planning for this study. This work was supported by grants NIH R01 CA050947 (to C.S.M.), CA179483 (to C.S.M. and N.S.G.), CA196664 (to C.S.M. and R.W.J.G.), CA180475 (to J.D.L. and C.S.M.), and U01 CA225730 (to C.S.M.), and U01CA176058 (to W.C.H.) and by the de Gunzburg Myeloma Research Fund (to C.S.M. and P.G.R.), the Ludwig Center at Harvard (to C.S.M.), the International Myeloma Foundation (to R.S. and G.M.M.), the Lauri Strauss Leukemia Foundation (to R.S.), a Leukemia and Lymphoma Society (LLS) Scholar Award (to C.S.M.), the LLS Translational Research Program (to C.S.M. and R.W.J.G.), the LLS Quest for Cure Program (to C.S.M. and R.W.J.G.), the Multiple Myeloma Research Foundation (MMRF) Answer Fund (to C.S.M. J.D.L. and L.H.B.), the MMRF Translational Network of Excellence (to C.S.M.), an MMRF Epigenetics Program Project grant (to J.D.L. and C.S.M.), the Shawna Ashlee Corman Investigatorship in Multiple Myeloma Research (to C.S.M.), the Cobb Family Myeloma Research Fund (to C.S.M.), the Chambers Family Advanced Myeloma Research Fund (to C.S.M. and P.G.R.), Department of Defense grants W81XWH-15-1-0012 (to C.S.M.) and W81XWH-15-1-0013 (to A.C.C.), the American-Australian Association (to G.M.M), Associazione Italiana per la Ricerca sul Cancro (to S.G.), and the Claudia Adams Barr Program in Innovative Basic Cancer Research at Dana-Farber Cancer Institute (to M.S. E.D. and C.S.M.). D.L.B. was a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG219614). Q.L.S. was supported by award T32GM007753 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. RPPA analyses were conducted by the Functional Proteomics RPPA Core facility, which is supported by MD Anderson Cancer Center support grant 5 P30 CA016672-40. R.S. G.M.M. S.G. J.R.V. J.B.B. O.D. H.P. H.T. M.A.B. M.S. Y.H. S.L.D-K. P.J.H. B.J.G. and E.D. performed experiments or assisted with generation of experimental data. R.d.M.S. P.J.H. A.C.C. F.V. and A.T performed computational analyses, wrote and implemented software for data analysis and visualization, and/or provided interpretation of results from CRISPR screens for treatment resistance or essentiality. D.L.B. Q.L.S. Y.H. T.Z. N.P.K. B.L.E. J.E.B. and N.S.G. provided preclinical reagents. J.P.L. R.L.S. and P.G.R. provided clinical samples. D.A. and J.L. provided, on behalf of the MMRF CoMMpass study, data on myeloma patient-derived samples, and these data were analyzed by R.d.M.S. D.A. J.L. J.D.L. L.H.B. and J.J.K. J.D.L. L.H.B. J.J.K. R.W.J.G. C.J.O, E.S.F. F.V. A.T. W.C.H. J.E.B. and N.S.G, provided advisory or supervisory roles in various components of the experimental procedures, computational analyses, and data interpretation. C.S.M. conceived and supervised the study, which was designed by R.S. G.M.M. R.d.M.S. and C.S.M. R.S. G.M.M. S.G. R.d.M.S. J.D.L. and C.S.M. wrote and/or revised the manuscript with assistance from the other authors. F.V. receives research funding from Novo Ventures. P.G.R. reports research support from Oncopeptides, Celgene/BMS, and Takeda and is an advisory committee member for Karyopharm, Oncopeptides, Celgene/BMS, Takeda, Janssen, Sanofi, Secura Bio, and GSK. E.S.F. is a founder, science advisory board member, and equity holder in Civetta, Jengu (board member), and Neomorph; an equity holder in C4; and a consultant to Astellas, Novartis, Deerfield, and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, Ajax, and Deerfield. N.P.K. is a consultant to Epiphanes, Inc. W.C.H. is a consultant for Thermo Fisher, Solvasta, MPM Capital, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicines, RAPPTA Therapeutics, and Parexel and is a founder of and advisor to KSQ Therapeutics. L.H.B. receives research funding from AstraZeneca and is a consultant for AstraZeneca and Genentech. B.L.E. has received research funding from Celgene and Deerfield. He has received consulting fees from GRAIL, and he serves on the scientific advisory boards for and holds equity in Skyhawk Therapeutics and Exo Therapeutics. J.E.B. is an author on United States patent applications licensed from the Dana-Farber Cancer Institute to C4 Therapeutics (TPD) and Tensha Therapeutics (now Roche; BRD4 inhibition). He is now an executive of and shareholder in Novartis AG. N.S.G. is a scientific founder, member of the scientific advisory board and equity holder in C4 Therapeutics, Syros Pharmaceuticals, Petra Pharmaceuticals, Ravenna, Inception, Allorion, Jengu, and Soltego (board member) and is the inventor on intellectual property licensed to these entities. R.S. G.M.M. S.G. R.d.M.S. and C.S.M. are authors on a patent application on the use of degraders. C.S.M. also discloses consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals and FIMECS; employment of a relative with Takeda; and research funding from Janssen/Johnson & Johnson, TEVA, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix. Funding Information: F.V. receives research funding from Novo Ventures. P.G.R. reports research support from Oncopeptides, Celgene/BMS, and Takeda and is an advisory committee member for Karyopharm, Oncopeptides, Celgene/BMS, Takeda, Janssen, Sanofi, Secura Bio, and GSK. E.S.F. is a founder, science advisory board member, and equity holder in Civetta, Jengu (board member), and Neomorph; an equity holder in C4; and a consultant to Astellas, Novartis, Deerfield, and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, Ajax, and Deerfield. N.P.K. is a consultant to Epiphanes, Inc. W.C.H. is a consultant for Thermo Fisher, Solvasta, MPM Capital, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicines, RAPPTA Therapeutics, and Parexel and is a founder of and advisor to KSQ Therapeutics. L.H.B. receives research funding from AstraZeneca and is a consultant for AstraZeneca and Genentech. B.L.E. has received research funding from Celgene and Deerfield. He has received consulting fees from GRAIL, and he serves on the scientific advisory boards for and holds equity in Skyhawk Therapeutics and Exo Therapeutics. J.E.B. is an author on United States patent applications licensed from the Dana-Farber Cancer Institute to C4 Therapeutics (TPD) and Tensha Therapeutics (now Roche; BRD4 inhibition). He is now an executive of and shareholder in Novartis AG. N.S.G. is a scientific founder, member of the scientific advisory board and equity holder in C4 Therapeutics, Syros Pharmaceuticals, Petra Pharmaceuticals, Ravenna, Inception, Allorion, Jengu, and Soltego (board member) and is the inventor on intellectual property licensed to these entities. R.S., G.M.M., S.G., R.d.M.S., and C.S.M. are authors on a patent application on the use of degraders. C.S.M. also discloses consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals and FIMECS; employment of a relative with Takeda; and research funding from Janssen/Johnson & Johnson, TEVA, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1/5

Y1 - 2021/1/5

N2 - 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.

AB - 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.

KW - CRBN

KW - CRISPR

KW - CRISPR activation

KW - E3 ligase

KW - PROTAC

KW - VHL

KW - heterobifunctional proteolysis-targeting chimeric compounds

KW - myeloma

KW - pharmacological degraders

KW - resistance

UR - http://www.scopus.com/inward/record.url?scp=85099249564&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.celrep.2020.108532

DO - https://doi.org/10.1016/j.celrep.2020.108532

M3 - Article

C2 - 33406420

SN - 2211-1247

VL - 34

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 108532

ER -

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

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