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

The unfolded protein response (UPR) promotes cell survival in cancers with hyperactive ER stress response. Here the authors show that CARM1, an arginine methyltransferase, controls the IRE1 alpha/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers. 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 IRE1 alpha/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1 alpha/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1 alpha/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, IRE1 alpha 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 IRE1 alpha/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

Automated summary

The arginine methyltransferase CARM1 regulates the IRE1 alpha/XBP1 pathway in the unfolded protein response, affecting the growth of ovarian cancers expressing CARM1. Inhibition of this pathway shows selective sensitivity in CARM1-expressing ovarian cancer cells. Pharmacological inhibition of the IRE1 alpha/XBP1 pathway alone or in combination with immune checkpoint blockade represents a potential therapeutic strategy for CARM1-expressing cancers.