Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in <i>ARID1A</i>-Mutant Ovarian Cancers.

Abstract

The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component <i>ARID1A</i> 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 <i>ARID1A</i>-mutant OCCC. <i>ARID1A</i> mutational status correlated with response to inhibition of the IRE1α-XBP1 pathway. In a conditional <i>Arid1a^flox/flox/Pik3ca^H1047R</i> genetic mouse model, <i>Xbp1</i> knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs <i>in vivo</i> 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 <i>ARID1A</i>-inactivated OCCCs. These studies define the IRE1α-XBP1 axis of the ER stress response as a targetable vulnerability for <i>ARID1A</i>-mutant OCCCs, revealing a promising therapeutic approach for treating <i>ARID1A</i>-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 <i>ARID1A</i>-mutant ovarian cancers.