Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.
Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.
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ARID1A是一种染色质重塑因子，在许多癌症类型中显示出最高的突变率之一。值得注意的是，ARID1A在超过50%的卵巢透明细胞癌中发生突变，目前尚无有效的治疗方法。迄今为止，基于ARID1A突变状态的临床适用的靶向癌症治疗尚未被描述。在这里，我们发现EZH2甲基转移酶的抑制在ARID1A突变的卵巢癌细胞中以合成致死方式起作用。ARID1A突变状态与对EZH2抑制剂的反应相关。我们发现PIK3IP1是ARID1A/EZH2的直接靶点，通过EZH2抑制上调，并通过抑制PI3K/AKT信号传导参与观察到的合成致死性。值得注意的是，EZH2抑制导致体内ARID1A突变的卵巢肿瘤消退。总之，这些数据首次证明了ARID1A突变和EZH2抑制之间的合成致死性。他们指出，药物抑制EZH2代表了ARID1A突变癌症的一种新的治疗策略。
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 has 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. ARID1A mutational status correlates with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct ARID1A/EZH2 target, which is upregulated by EZH2 inhibition and contributes to the observed synthetic lethality by inhibiting PI3K/AKT signaling. Significantly, EZH2 inhibition causes regression of ARID1A mutated ovarian tumors in vivo. Together, these data demonstrate for the first time a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.