Dual targeting of the DNA damage response pathway and BCL-2 in diffuse large B-cell lymphoma.
Adolescent
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
/ pharmacology
Biomarkers, Tumor
/ genetics
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
DNA Repair Enzymes
/ antagonists & inhibitors
Drug Therapy, Combination
Female
Follow-Up Studies
Gene Expression Regulation, Leukemic
/ drug effects
Humans
Lymphoma, Large B-Cell, Diffuse
/ drug therapy
Male
Middle Aged
Prognosis
Prospective Studies
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Retrospective Studies
Sulfonamides
/ pharmacology
Survival Rate
Thiophenes
/ pharmacology
Urea
/ analogs & derivatives
Young Adult
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
01
11
2020
accepted:
08
07
2021
revised:
28
06
2021
pubmed:
26
7
2021
medline:
19
2
2022
entrez:
25
7
2021
Statut:
ppublish
Résumé
Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient's population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.
Identifiants
pubmed: 34304248
doi: 10.1038/s41375-021-01347-6
pii: 10.1038/s41375-021-01347-6
pmc: PMC8727301
doi:
Substances chimiques
3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
0
Antineoplastic Agents
0
BCL2 protein, human
0
Biomarkers, Tumor
0
Bridged Bicyclo Compounds, Heterocyclic
0
Proto-Oncogene Proteins c-bcl-2
0
Sulfonamides
0
Thiophenes
0
Urea
8W8T17847W
DNA Repair Enzymes
EC 6.5.1.-
venetoclax
N54AIC43PW
Types de publication
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
197-209Informations de copyright
© 2021. The Author(s).
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