Systematic characterization of therapeutic vulnerabilities in Multiple Myeloma with Amp1q reveals increased sensitivity to the combination of MCL1 and PI3K inhibitors.

1q21 Amp1q CRISPR screen MCL1 Multiple Myeloma PI3K RNAi screen chr1q drug screen precision therapy targeted therapy

Journal

bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187

Informations de publication

Date de publication:
03 Aug 2023
Historique:
pubmed: 14 8 2023
medline: 14 8 2023
entrez: 14 8 2023
Statut: epublish

Résumé

The development of targeted therapy for patients with Multiple Myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chr1q (Amp1q) is the most frequent arm-level copy number gain in patients with MM, and it is associated with higher risk of progression and death despite recent advances in therapeutics. Thus, developing targeted therapy for patients with MM and Amp1q stands to benefit a large portion of patients in need of more effective management. Here, we employed large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with Amp1q and showed increased sensitivity to the combination of MCL1 and PI3K inhibitors. Using single-cell RNA sequencing, we compared subclones with and without Amp1q within the same patient tumors and showed that Amp1q is associated with higher levels of

Identifiants

DOI: 10.1101/2023.08.01.551480 PMID: 37577538 PMC: PMC10418223
pubmed: 37577538
doi: 10.1101/2023.08.01.551480
pmc: PMC10418223
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NCI NIH HHS
ID : R01 CA266298
Pays : United States

Déclaration de conflit d'intérêts

DECLARATION OF INTEREST E.D.L., M.R., J.T., M.P.A., D.H.M., D.H., S.J.F.C., L.H., N.J.H., T.W., N.K.S., B.B., J.A., and M.P. declare no competing interests. R.S.P. is a co-founder and equity holder in PreDICTA Biosciences. M.S.D. has received research funding from AbbVie, AstraZeneca, Ascentage Pharma, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics and personal consulting income from AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Janssen, Merck, Mingsight Pharmaceuticals, Nuvalent, Secura Bio, TG Therapeutics, and Takeda. G.G. receives research funds from IBM, Pharmacyclics, and Ultima Genomics and is an inventor on patent applications filed by the Broad Institute related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSIDetect, and MinumuMM-seq. He is also a founder, consultant, and holds privately held equity in Scorpion Therapeutics and PreDICTA Biosciences. I.M.G. has a consulting or advisory role with AbbVie, Adaptive, Amgen, Aptitude Health, Bristol Myers Squibb, GlaxoSmithKline, Huron Consulting, Janssen, Menarini Silicon Biosystems, Oncopeptides, Pfizer, Sanofi, Sognef, Takeda, The Binding Site, and Window Therapeutics; has received speaker fees from Vor Biopharma and Veeva Systems, Inc.; is a co-founder and equity holder in PreDICTA Biosciences; and her spouse is the CMO and equity holder of Disc Medicine. S.M. has a consulting role with Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Regeneron, Roche, Takeda, and has received research funding from Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Regeneron, Roche, Takeda.

Auteurs

Romanos Sklavenitis-Pistofidis (R)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Elizabeth D Lightbody (ED)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Mairead Reidy (M)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Junko Tsuji (J)

Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Michelle P Aranha (MP)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Daniel Heilpern-Mallory (D)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Daisy Huynh (D)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Stephen J F Chong (SJF)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Liam Hackett (L)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Nicholas J Haradhvala (NJ)

Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Ting Wu (T)

Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Nang K Su (NK)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Brianna Berrios (B)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Jean-Baptiste Alberge (JB)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Ankit Dutta (A)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Matthew S Davids (MS)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Maria Papaioannou (M)

Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Hematology Unit, 1st Internal Medicine Department, AHEPA University Hospital, Thessaloniki, Greece.

Gad Getz (G)

Harvard Medical School, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Irene M Ghobrial (IM)

Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Salomon Manier (S)

INSERM UMRS1277, CNRS UMR9020, Lille University, 59000, France.
Department of Hematology, CHU Lille, Lille University, 59000, France.

Classifications MeSH