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. 2019 Jan 11;10:137. doi: 10.1038/s41467-018-08150-5

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — Mechanism of combinatory activity between SF3b-targeting splicing modulators and BCLxL/BCL2 inhibitors. SF3b-targeting splicing modulators preferentially perturb the RNA splicing of MCL1 and BCL2A1 but not BCL2L1 (BCLxL), leading to selective cytotoxicity in MCL1- or BCL2A1-dependent cancer cells. In combination with BCLxL/BCL2 inhibitors, splicing modulators can enhance the cytotoxicity through a broader inhibition of the BCL2 family genes that act cooperatively in antiapoptosis/pro-survival in cancer cells. These findings inform mechanism-based approaches to the future clinical development of splicing modulators in cancer treatment. This combination strategy may offer effective repression of most of the cancer-relevant antiapoptotic BCL2 family members, thus broadening the impact of both compounds to a variety of indications, and potentially overcoming the resistance to the current BCL2/BCLxL-targeting agents. BCL2 family genes: red, confirmed oncogene-addiction role; gray: undetermined role