Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 21, 2021
- Source ID
- 10.1158/0008-5472.can-21-1545
Entities
People
- Andrew V Kossenkov
- Chih-Chi Andrew Hu
- Jianhuang Lin
- Joel Cassel
- Joseph A. Zundell
- Nail Fatkhudinov
- Qin Liu
- Rugang Zhang
- Shuai Wu
- Takeshi Fukumoto
- Timothy Nacarelli
Organizations
- Honorable Tina Brozman Foundation
- National Institutes of Health
- Ovarian Cancer Research Alliance
- United States Department of Defense
- University of Science Malaysia
- Wistar Institute