BCL-XL is an actionable target for treatment of malignant pleural mesothelioma.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
31 Oct 2020
31 Oct 2020
Historique:
received:
23
08
2020
accepted:
20
09
2020
entrez:
10
12
2020
pubmed:
11
12
2020
medline:
11
12
2020
Statut:
epublish
Résumé
Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.
Identifiants
pubmed: 33298868
doi: 10.1038/s41420-020-00348-1
pii: 10.1038/s41420-020-00348-1
pmc: PMC7603509
doi:
Types de publication
Journal Article
Langues
eng
Pagination
114Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : GNT1166447
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : GNT1157551
Organisme : Department of Education and Training | Australian Research Council (ARC)
ID : FT150100212
Organisme : Victorian Cancer Agency (VCA)
ID : MCRF19045
Commentaires et corrections
Type : ErratumIn
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