Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Jianhuang Lin, Heng Liu, Takeshi Fukumoto, Joseph Zundell, Qingqing Yan, Chih-Hang Anthony Tang, Shuai Wu, Wei Zhou, Dajiang Guo, Sergey Karakashev, Chih-Chi Andrew Hu, Kavitha Sarma, Andrew V. Kossenkov and Rugang Zhang ()
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Jianhuang Lin: The Wistar Institute
Heng Liu: The Wistar Institute
Takeshi Fukumoto: The Wistar Institute
Joseph Zundell: The Wistar Institute
Qingqing Yan: The Wistar Institute
Chih-Hang Anthony Tang: Houston Methodist Research Institute
Shuai Wu: The Wistar Institute
Wei Zhou: The Wistar Institute
Dajiang Guo: The Wistar Institute
Sergey Karakashev: The Wistar Institute
Chih-Chi Andrew Hu: Houston Methodist Research Institute
Kavitha Sarma: The Wistar Institute
Andrew V. Kossenkov: The Wistar Institute
Rugang Zhang: The Wistar Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

Date: 2021
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DOI: 10.1038/s41467-021-25684-3

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