The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Here, we report that ARID1A transcriptionally represses the IRE1α–XBP1 axis of the endoplasmic reticulum (ER) stress response, which confers sensitivity to inhibition of the IRE1α–XBP1 pathway in ARID1A -mutant OCCC. ARID1A mutational status correlated with response to inhibition of the IRE1α–XBP1 pathway. In a conditional Arid1aflox/flox/Pik3caH1047R genetic mouse model, Xbp1 knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs in vivo in orthotopic xenograft, patient-derived xenograft, and the genetic mouse models. Finally, B-I09 synergized with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A -inactivated OCCCs. These studies define the IRE1α−XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A -mutant OCCCs, revealing a promising therapeutic approach for treating ARID1A -mutant ovarian cancers. Significance: These findings indicate that pharmacological inhibition of the IRE1α–XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A -mutant ovarian cancers.

中文翻译：

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靶向 ARID1A 突变卵巢癌中的 IRE1{alpha}/XBP1 内质网应激反应途径

SWI/SNF 染色质重塑复合物在人类癌症中经常发生改变。例如，SWI/SNF 成分 ARID1A 在超过 50% 的卵巢透明细胞癌 (OCCC) 中发生突变，缺乏有效的治疗方法。在这里，我们报告 ARID1A 转录抑制内质网 (ER) 应激反应的 IRE1α-XBP1 轴，这赋予了 ARID1A 突变体 OCCC 中抑制 IRE1α-XBP1 通路的敏感性。ARID1A 突变状态与抑制 IRE1α-XBP1 通路的反应相关。在条件性 Arid1aflox/flox/Pik3caH1047R 遗传小鼠模型中，Xbp1 敲除显着提高了携带 OCCC 小鼠的存活率。此外，IRE1α 抑制剂 B-I09 在原位异种移植、患者来源的异种移植和遗传小鼠模型中抑制了 ARID1A 灭活的 OCCC 在体内的生长。最后，B-I09 与抑制 HDAC6（一种已知的 ER 应激反应调节剂）协同抑制 ARID1A 灭活的 OCCC 的生长。这些研究将 ER 应激反应的 IRE1α-XBP1 轴定义为 ARID1A 突变型 OCCC 的可靶向脆弱性，揭示了一种治疗 ARID1A 突变型卵巢癌的有希望的治疗方法。意义：这些发现表明，IRE1α-XBP1 通路的药理学抑制单独或与 HDAC6 抑制联合是 ARID1A 突变卵巢癌急需的治疗策略。这些研究将 ER 应激反应的 IRE1α-XBP1 轴定义为 ARID1A 突变型 OCCC 的可靶向脆弱性，揭示了一种治疗 ARID1A 突变型卵巢癌的有希望的治疗方法。意义：这些发现表明，IRE1α-XBP1 通路的药理学抑制单独或与 HDAC6 抑制联合是 ARID1A 突变卵巢癌急需的治疗策略。这些研究将 ER 应激反应的 IRE1α-XBP1 轴定义为 ARID1A 突变型 OCCC 的可靶向脆弱性，揭示了一种治疗 ARID1A 突变型卵巢癌的有希望的治疗方法。意义：这些发现表明，IRE1α-XBP1 通路的药理学抑制单独或与 HDAC6 抑制联合是 ARID1A 突变卵巢癌急需的治疗策略。