Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators

Daniel Aird, Teng Teng, Chia-Ling Huang, Ermira Pazolli, Deepti Banka, Kahlin Cheung-Ong, Cheryl Eifert, Craig Furman, Zhenhua Jeremy Wu, Michael Seiler, Silvia Buonamici, Peter Fekkes, Craig Karr, James Palacino, Eunice Park, Peter G. Smith, Lihua Yu, Yoshiharu Mizui, Markus Warmuth, Agustin Chicas, Laura Corson and Ping Zhu ()
Additional contact information
Daniel Aird: H3 Biomedicine, Inc.
Teng Teng: H3 Biomedicine, Inc.
Chia-Ling Huang: H3 Biomedicine, Inc.
Ermira Pazolli: H3 Biomedicine, Inc.
Deepti Banka: H3 Biomedicine, Inc.
Kahlin Cheung-Ong: H3 Biomedicine, Inc.
Cheryl Eifert: H3 Biomedicine, Inc.
Craig Furman: H3 Biomedicine, Inc.
Zhenhua Jeremy Wu: H3 Biomedicine, Inc.
Michael Seiler: H3 Biomedicine, Inc.
Silvia Buonamici: H3 Biomedicine, Inc.
Peter Fekkes: H3 Biomedicine, Inc.
Craig Karr: H3 Biomedicine, Inc.
James Palacino: H3 Biomedicine, Inc.
Eunice Park: H3 Biomedicine, Inc.
Peter G. Smith: H3 Biomedicine, Inc.
Lihua Yu: H3 Biomedicine, Inc.
Yoshiharu Mizui: H3 Biomedicine, Inc.
Markus Warmuth: H3 Biomedicine, Inc.
Agustin Chicas: H3 Biomedicine, Inc.
Laura Corson: H3 Biomedicine, Inc.
Ping Zhu: H3 Biomedicine, Inc.

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-018-08150-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08150-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-08150-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().