Abstract
Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity1. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.
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Acknowledgements
EZ005 was provided courtesy of J. Bradner (Dana-Farber Cancer Institute). Plasmids for wild-type and SET domain–truncated (SET) EZH2 were provided courtesy of M. Brown (Dana-Farber Cancer Institute). K.H.K. was supported by an award from National Cancer Center. This work was supported by US National Institutes of Health grants R01CA172152 (C.W.M.R.), R01CA113794 (C.W.M.R.) and U01CA176058 (W.C.H.). W.K. was supported by a Claudia Adams Barr grant. T.P.H. was supported by an award from the National Institute of General Medical Sciences (T32GM007753). The Cure AT/RT Now foundation, the Avalanna Fund, the Garrett B. Smith Foundation, Miles for Mary (C.W.M.R.), a Leukemia & Lymphoma Society Specialized Center of Research Award Project Grant (L.D.W.) and the Todd J. Schwartz Memorial Fund (L.D.W.) provided additional support.
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K.H.K. and C.W.M.R. designed the study; K.H.K., W.W. and J.R.H. performed the experiments with the help of J.N.W.; W.K., S.H.O. and L.D.W. provided stapled peptides and contributed to data analysis; T.P.H., W.C.H., F.V. and A.T. analyzed Achilles data; K.H.K. and C.W.M.R. wrote the manuscript with comments from all authors.
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L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics. Via the Dana-Farber Cancer Institute Novartis Drug Discovery Program, C.W.M.R. and W.C.H. receive research support and consulting fees from the Novartis Institutes for Biomedical Research.
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Supplementary Text and Figures
Supplementary Figures 1–5 & Supplementary Table 1 (PDF 1940 kb)
Supplementary Data 1
Project Achilles data and mutation annotations (XLSX 39 kb)
Supplementary Data 2
Mutations in cell lines used in this study (XLSX 47 kb)
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Kim, K., Kim, W., Howard, T. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med 21, 1491–1496 (2015). https://doi.org/10.1038/nm.3968
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DOI: https://doi.org/10.1038/nm.3968
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