Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators.
A549 Cells
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Apoptosis Regulatory Proteins
/ genetics
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
Doxycycline
/ pharmacology
Drug Synergism
Epoxy Compounds
/ pharmacology
Female
Humans
Lung Neoplasms
/ drug therapy
Macrolides
/ pharmacology
Melanoma
/ drug therapy
Mice
Mice, Nude
Minor Histocompatibility Antigens
/ genetics
Myeloid Cell Leukemia Sequence 1 Protein
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ genetics
RNA Interference
RNA Splicing
/ drug effects
RNA, Small Interfering
/ genetics
Spliceosomes
/ drug effects
Exome Sequencing
Xenograft Model Antitumor Assays
bcl-X Protein
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 01 2019
11 01 2019
Historique:
received:
10
07
2018
accepted:
18
12
2018
entrez:
13
1
2019
pubmed:
13
1
2019
medline:
9
2
2019
Statut:
epublish
Résumé
Dysregulation of RNA splicing by spliceosome mutations or in cancer genes is increasingly recognized as a hallmark of cancer. Small molecule splicing modulators have been introduced into clinical trials to treat solid tumors or leukemia bearing recurrent spliceosome mutations. Nevertheless, further investigation of the molecular mechanisms that may enlighten therapeutic strategies for splicing modulators is highly desired. Here, using unbiased functional approaches, we report that the sensitivity to splicing modulation of the anti-apoptotic BCL2 family genes is a key mechanism underlying preferential cytotoxicity induced by the SF3b-targeting splicing modulator E7107. While BCL2A1, BCL2L2 and MCL1 are prone to splicing perturbation, BCL2L1 exhibits resistance to E7107-induced splicing modulation. Consequently, E7107 selectively induces apoptosis in BCL2A1-dependent melanoma cells and MCL1-dependent NSCLC cells. Furthermore, combination of BCLxL (BCL2L1-encoded) inhibitors and E7107 remarkably enhances cytotoxicity in cancer cells. These findings inform mechanism-based approaches to the future clinical development of splicing modulators in cancer treatment.
Identifiants
pubmed: 30635584
doi: 10.1038/s41467-018-08150-5
pii: 10.1038/s41467-018-08150-5
pmc: PMC6329755
doi:
Substances chimiques
Antineoplastic Agents
0
Apoptosis Regulatory Proteins
0
BCL2-related protein A1
0
BCL2L1 protein, human
0
BCL2L2 protein, human
0
E 7107
0
Epoxy Compounds
0
MCL1 protein, human
0
Macrolides
0
Minor Histocompatibility Antigens
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
RNA, Small Interfering
0
bcl-X Protein
0
Doxycycline
N12000U13O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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