Nature communications, 2019-01, Vol.10 (1), p.137-137, Article 137
- Aird, Daniel
- Teng, Teng
- Huang, Chia-Ling
- Pazolli, Ermira
- Banka, Deepti
- Cheung-Ong, Kahlin
- Eifert, Cheryl
- Furman, Craig
- Wu, Zhenhua Jeremy
- Seiler, Michael
- Buonamici, Silvia
- Fekkes, Peter
- Karr, Craig
- Palacino, James
- Park, Eunice
- Smith, Peter G.
- Yu, Lihua
- Mizui, Yoshiharu
- Warmuth, Markus
- Chicas, Agustin
- Corson, Laura
- Zhu, Ping
2019
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- Autor(en) / Beteiligte
- Aird, Daniel
- Teng, Teng
- Huang, Chia-Ling
- Pazolli, Ermira
- Banka, Deepti
- Cheung-Ong, Kahlin
- Eifert, Cheryl
- Furman, Craig
- Wu, Zhenhua Jeremy
- Seiler, Michael
- Buonamici, Silvia
- Fekkes, Peter
- Karr, Craig
- Palacino, James
- Park, Eunice
- Smith, Peter G.
- Yu, Lihua
- Mizui, Yoshiharu
- Warmuth, Markus
- Chicas, Agustin
- Corson, Laura
- Zhu, Ping
- Titel
- Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators
- Ist Teil von
- Nature communications, 2019-01, Vol.10 (1), p.137-137, Article 137
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. Small molecule modulators of RNA splicing have therapeutic potential in tumours bearing spliceosome mutations. Here, the authors identify BCL2 genes have differential sensitivities to SF3b-targeting splicing modulators and combination of SF3b-targeting splicing modulators and BCLxL inhibition induces synergistic cytotoxicity in cancer cells.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-018-08150-5Titel-ID: cdi_doaj_primary_oai_doaj_org_article_3d3b4213a3e7400997cdfc63d11b14e8
- Format
- –
- Schlagworte
- 13, 13/1, 13/89, 38/47, 38/91, 45, 45/77, 49, 631/154, 631/67, 692/4017, A549 Cells, Animals, Antineoplastic Agents - pharmacology, Apoptosis - drug effects, Apoptosis Regulatory Proteins - genetics, bcl-X Protein - genetics, Cancer, Carcinoma, Non-Small-Cell Lung - drug therapy, Carcinoma, Non-Small-Cell Lung - genetics, Cell Line, Tumor, Computer applications, Cytotoxicity, Doxycycline - pharmacology, Drug Synergism, Epoxy Compounds - pharmacology, Female, Gene expression, Humanities and Social Sciences, Humans, Lung Neoplasms - drug therapy, Lung Neoplasms - genetics, Macrolides - pharmacology, Melanoma - drug therapy, Melanoma - genetics, Mice, Mice, Nude, Minor Histocompatibility Antigens - genetics, multidisciplinary, Mutation, Myeloid Cell Leukemia Sequence 1 Protein - genetics, Non-small cell lung carcinoma, Proto-Oncogene Proteins c-bcl-2 - genetics, Ribonucleic acid, RNA, RNA Interference, RNA Splicing - drug effects, RNA Splicing - genetics, RNA, Small Interfering - genetics, Science, Science (multidisciplinary), Software, Spliceosomes - drug effects, Spliceosomes - genetics, Whole Exome Sequencing, Xenograft Model Antitumor Assays