Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma.
Activating Transcription Factor 3
/ metabolism
Adenine
/ analogs & derivatives
Bridged Bicyclo Compounds, Heterocyclic
/ therapeutic use
Cell Line, Tumor
Chromatin
/ metabolism
Chromosomal Proteins, Non-Histone
/ genetics
Circulating Tumor DNA
/ genetics
Cohort Studies
DNA Helicases
/ metabolism
Drug Resistance, Neoplasm
/ genetics
Genome, Human
Humans
Lymphoma, Mantle-Cell
/ drug therapy
Models, Biological
Mutation
/ genetics
Nuclear Proteins
/ metabolism
Piperidines
Prognosis
Pyrazoles
/ therapeutic use
Pyrimidines
/ therapeutic use
Sulfonamides
/ therapeutic use
Transcription Factors
/ genetics
Treatment Outcome
bcl-X Protein
/ metabolism
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
09
03
2018
accepted:
21
09
2018
pubmed:
21
11
2018
medline:
11
5
2019
entrez:
21
11
2018
Statut:
ppublish
Résumé
Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies.
Identifiants
pubmed: 30455436
doi: 10.1038/s41591-018-0243-z
pii: 10.1038/s41591-018-0243-z
doi:
Substances chimiques
ATF3 protein, human
0
Activating Transcription Factor 3
0
Bridged Bicyclo Compounds, Heterocyclic
0
Chromatin
0
Chromosomal Proteins, Non-Histone
0
Circulating Tumor DNA
0
Nuclear Proteins
0
Piperidines
0
Pyrazoles
0
Pyrimidines
0
SWI-SNF-B chromatin-remodeling complex
0
Sulfonamides
0
Transcription Factors
0
bcl-X Protein
0
ibrutinib
1X70OSD4VX
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Adenine
JAC85A2161
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
119-129Subventions
Organisme : Leukemia and Lymphoma Society (LLS)
ID : 0862-15
Pays : International
Organisme : Howard Hughes Medical Institute (HHMI)
ID : 55008729
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1104549
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1114242
Pays : International
Organisme : Leukemia and Lymphoma Society (LLS)
ID : 0862-15
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1104549
Pays : International
Organisme : Leukemia and Lymphoma Society (LLS)
ID : 0862-15
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1104549
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1079560
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1113577
Pays : International
Organisme : Leukemia and Lymphoma Society (LLS)
ID : 0862-15
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1104549
Pays : International
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : 1090236
Pays : International
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