The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K–AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
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We thank D. Altieri, M. Murphy and R. Shiekhattar for critical comments and X. Hua and Y. Park for technical assistance. This work was supported by grants from the US National Institutes of Health/National Cancer Institute (R01CA160331 and R01CA163377 to R.Z.), a US Department of Defense Ovarian Cancer Academy award (OC093420 to R.Z.) and an Ovarian Cancer Research Fund Program project (to R.Z.). R.Z. is an Ovarian Cancer Research Fund Liz Tilberis Scholar. B.G.B. is supported by an American Cancer Society postdoctoral fellowship (PF-13-058-01-TBE). K.M.A. is supported by a training grant from the US National Institutes of Health/National Cancer Institute (T32CA9171-35). Support of Core Facilities was provided by Cancer Center Support grant CA010815 to the Wistar Institute.
The authors declare no competing financial interests.
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Bitler, B., Aird, K., Garipov, A. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 21, 231–238 (2015). https://doi.org/10.1038/nm.3799
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