2. Academic Validation
  3. Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers

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

  • Cancer Res. 2021 Oct 15;81(20):5325-5335. doi: 10.1158/0008-5472.CAN-21-1545.
Joseph A Zundell 1 2,  Takeshi Fukumoto 1,  Jianhuang Lin 1,  Nail Fatkhudinov 1,  Timothy Nacarelli 1,  Andrew V Kossenkov 3,  Qin Liu 4,  Joel Cassel 5,  Chih-Chi Andrew Hu 6,  Shuai Wu 7,  Rugang Zhang 7
Affiliations

Affiliations

  • 1 Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
  • 2 Department of Biological Sciences, Misher College of Arts and Sciences, University of Science, Philadelphia, Pennsylvania.
  • 3 Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.
  • 4 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
  • 5 Molecular Screening and Protein Expression Facility, The Wistar Institute, Philadelphia, Pennsylvania.
  • 6 Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, Texas.
  • 7 Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania. rzhang@wistar.org swu@wistar.org.
PMID: 34548333 DOI: 10.1158/0008-5472.CAN-21-1545
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. 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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