ArticleCell reports2021
Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.
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In one paragraph
Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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53citing papers in PubMed, 1 pooled it
6.9field-weighted citation impact, top 2% of its field
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 106 citations in OpenAlex.
- Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation.Nature chemical biology · 2026Article
- Advancing PROTAC therapeutics through chemistry-guided design of smart delivery systems.Acta pharmacologica Sinica · 2026Review
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- Targeted KRASG12V Degradation In Vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis.Cancer research · 2026Article
- PAX3::FOXO1-Targeting PROTAC Induces Myogenic Differentiation of Fusion-Positive Rhabdomyosarcoma Cells.Cancers · 2026Article
- Deciphering resistance mechanisms to auxin-inducible protein degradation in mammalian cells.The Journal of biological chemistry · 2026Article
- From undruggable to degradable: A deep learning-enabled framework for precision orthopaedic protein degradation.Journal of orthopaedic translation · 2026Review
- Targeted degradation of c-Myc through the midnolin-proteasome pathway.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- Indirect ubiquitination independent of endogenous ubiquitination machinery for targeted protein degradation.Communications chemistry · 2026Article
- Ion channel inhibition by targeted recruitment of NEDD4-2 with divalent nanobodies.Nature communications · 2025Article
- Recent advances in targeting protein degradation for tumor immunotherapy.Journal of hematology & oncology · 2025Review
- Deciphering acquired resistance mechanisms to sustained auxin-inducible protein degradation in cells and mice.bioRxiv : the preprint server for biology · 2025Article
- Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation.Nature structural & molecular biology · 2025Article
- Advancing Design Strategy of PROTACs for Cancer Therapy.MedComm · 2025Review
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- Cellular parameters shaping pathways of targeted protein degradation.Communications biology · 2025Review
- Rational Design of PROTAC Linkers Featuring Ferrocene as a Molecular Hinge to Enable Dynamic Conformational Changes.Journal of the American Chemical Society · 2025Article
Corrections and comments
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Authors and funding
39 authors at 8 institutions in 2 countries.
Ryosuke ShirasakiDepartment 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.
Geoffrey M MatthewsDepartment 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.
Sara GandolfiDepartment 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.
Ricardo de Matos SimoesDepartment 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.
Dennis L BuckleyDepartment 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.
Joseline Raja VoraDepartment 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.
Quinlan L SieversDepartment 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.
Johanna B BrüggenthiesDepartment 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.
Olga DashevskyDepartment 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.
Haley PoarchDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Huihui TangDepartment 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.
Megan A BariteauDepartment 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.
Michal ShefferDepartment 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.
Yiguo HuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Sondra L Downey-KopyscinskiDepartment 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.
Paul J HengeveldDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Brian J GlassnerDepartment 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.
Eugen DhimoleaDepartment 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.
Christopher J OttDepartment 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.
Tinghu ZhangHarvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nicholas P KwiatkowskiHarvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jacob P LaubachDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Robert L SchlossmanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Paul G RichardsonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Aedin C CulhaneDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Richard W J GroenDepartment of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands.
Eric S FischerHarvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Francisca VazquezBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Aviad TsherniakBroad Institute of MIT and Harvard, Cambridge, MA, USA.
William C HahnDepartment 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.
Joan LevyMultiple Myeloma Research Foundation, Norwalk, CT, USA.
Daniel AuclairMultiple Myeloma Research Foundation, Norwalk, CT, USA.
Jonathan D LichtUniversity of Florida Health Cancer Center, Gainesville, FL, USA.
Jonathan J KeatsTranslational Genomics Research Institute, Phoenix, AZ, USA.
Lawrence H BoiseDepartment of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Benjamin L EbertDepartment 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.
James E BradnerDepartment 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.
Nathanael S GrayHarvard Medical School, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Constantine S MitsiadesDepartment 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.
Broad Institute · USHarvard University · USDana-Farber Cancer Institute · USMultiple Myeloma Research Foundation · USCancer Center Amsterdam · NLEmory University · USTranslational Genomics Research Institute · USUniversity of Florida Health · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MMedical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MThe Dana-Farber Cancer Institute Cancer Target Discovery and Development CenterU01CA176058 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2013 to 2021
$7.8MRole of Cytokines in Myeloma PathogenesisR01CA050947 · NCI · DANA-FARBER CANCER INSTITUTE · PI ANDERSON, KENNETH C., MITSIADES, CONSTANTINE S. · 1991 to 2018
$5.1MAnalysis of E-selectin Ligands of Human Acute Leukemia Cells and their Biology in LeukemogenesisU01CA225730 · NCI · FLORIDA INTERNATIONAL UNIVERSITY · PI MITSIADES, CONSTANTINE S., SACKSTEIN, ROBERT · 2019 to 2023
$3.0MUTX, MLL AND PATHOGENIC DEREGULATION OF HISTONE METHYLATION IN MULTIPLE MYELOMAR01CA180475 · NCI · UNIVERSITY OF FLORIDA · PI LICHT, JONATHAN D. · 2014 to 2020
$1.8MHumanized bone marrow-like model to study patient-derived myeloma xenograftsR01CA196664 · NCI · DANA-FARBER CANCER INST · PI GROEN, RICHARD, MITSIADES, CONSTANTINE S. · 2016 to 2018
$1.6MDevelopment and Application of Selective Covalent Cdk7 InhibitorsR01CA179483 · NCI · DANA-FARBER CANCER INST · PI GRAY, NATHANAEL SCHIANDER, MITSIADES, CONSTANTINE S. · 2014 to 2016
$1.5MChemical Modulation of Chromatin Signaling in Lymphoid MalignanciesR00CA190861 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI OTT, CHRISTOPHER J · 2017 to 2019
$737kNCI NIH HHS P30 CA016672NCI NIH HHS R00 CA190861NCI NIH HHS R01 CA050947NCI NIH HHS R01 CA179483NCI NIH HHS R01 CA180475NCI NIH HHS R01 CA196664NCI NIH HHS U01 CA176058NCI NIH HHS U01 CA225730NIGMS NIH HHS T32 GM007753
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.
Indexed as
Adaptor Proteins, Signal TransducingAnimalsAntineoplastic AgentsBromodomain Containing ProteinsCell Line, TumorCRISPR-Cas SystemsCyclin-Dependent Kinase 9Drug Resistance, NeoplasmGene EditingGene Expression Regulation, NeoplasticGenes, OverlappingGenome-Wide Association StudyGenomicsHumansMiceMultiple MyelomaAdaptor Proteins, Signal TransducingAntineoplastic Agentsbromodomain and extra-terminal domain protein, humanBromodomain Containing ProteinsCDK9 protein, humanCRBN protein, humanCULL-RING ligase, humanCyclin-Dependent Kinase 9Oncogene ProteinsProteinsUbiquitin-Protein LigasesVon Hippel-Lindau Tumor Suppressor ProteinCRBNCRISPRCRISPR activationE3 ligaseheterobifunctional proteolysis-targeting chimeric compoundsmyelomapharmacological degradersPROTACresistanceVHL
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