TY - JOUR
T1 - Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers
AU - Zundell, Joseph A.
AU - Fukumoto, Takeshi
AU - Lin, Jianhuang
AU - Fatkhudinov, Nail
AU - Nacarelli, Timothy
AU - Kossenkov, Andrew V.
AU - Liu, Qin
AU - Cassel, Joel
AU - Hu, Chih Chi Andrew
AU - Wu, Shuai
AU - Zhang, Rugang
N1 - ©2021 American Association for Cancer Research.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-21-1545
DO - 10.1158/0008-5472.CAN-21-1545
M3 - Article
C2 - 34548333
SN - 0008-5472
VL - 81
SP - 5325
EP - 5335
JO - Cancer research
JF - Cancer research
IS - 20
ER -