Bitler Benjamin G, Aird Katherine M, Garipov Azat, Li Hua, Amatangelo Michael, Kossenkov Andrew V, Schultz David C, Liu Qin, Shih Ie-Ming, Conejo-Garcia Jose R, Speicher David W, Zhang Rugang
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Nat Med. 2015 Mar;21(3):231-8. doi: 10.1038/nm.3799. Epub 2015 Feb 16.
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.
编码染色质重塑因子ARID1A的基因在多种癌症类型中显示出最高的突变率之一。值得注意的是，超过50%的卵巢透明细胞癌中存在ARID1A突变，而目前这些癌症尚无有效的治疗方法。迄今为止，尚未有基于ARID1A突变状态的临床适用的靶向癌症治疗方法的报道。在此，我们表明抑制EZH2甲基转移酶在ARID1A突变的卵巢癌细胞中以合成致死的方式起作用，并且ARID1A突变状态与对EZH2抑制剂的反应相关。我们确定PIK3IP1是ARID1A和EZH2的直接靶点，EZH2抑制可使其上调，并通过抑制PI3K-AKT信号传导导致观察到的合成致死性。重要的是，EZH2抑制在体内导致ARID1A突变的卵巢肿瘤消退。据我们所知，这是首个证明ARID1A突变与EZH2抑制之间存在合成致死性的数据集。我们的数据表明，EZH2的药理学抑制代表了一种针对涉及ARID1A突变的癌症的新型治疗策略。
