Journal Article

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

Tang, Chih-Hang Anthony, Kossenkov, Andrew V., Fukumoto, Takeshi, Hu, Chih-Chi Andrew, Guo, Dajiang, Zhou, Wei, Zundell, Joseph, Wu, Shuai, Yan, Qingqing, Lin, Jianhuang, Zhang, Rugang, Karakashev, Sergey, Sarma, Kavitha, Liu, Heng

2021

Overview

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. 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 IRE1α/XBP1 pathway of the UPR and the inhibition of this pathway can inhibit growth in CARM1 expressing ovarian cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/2 / 13/31 / 13/89 / 38/15 / 38/22 / 38/39 / 38/77 / 631/80/82/23 / 692/4028/67/1517/1709 / Animals / Antibodies / Antibodies, Monoclonal - pharmacology / Base Sequence / Benzopyrans - pharmacology / Cancer / Carcinoma, Ovarian Epithelial - genetics / Carcinoma, Ovarian Epithelial - immunology / Carcinoma, Ovarian Epithelial - pathology / Carcinoma, Ovarian Epithelial - therapy / Cell Line, Tumor / Cell survival / Cellular stress response / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Endoribonucleases - antagonists & inhibitors / Endoribonucleases - genetics / Endoribonucleases - immunology / Female / Gene expression / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Hymecromone - analogs & derivatives / Hymecromone - pharmacology / Immune checkpoint / Immune Checkpoint Inhibitors / Kinases / Mice / Molecular Targeted Therapy / multidisciplinary / Ovarian cancer / Ovarian Neoplasms - genetics / Ovarian Neoplasms - immunology / Ovarian Neoplasms - pathology / Ovarian Neoplasms - therapy / PD-1 protein / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Protein arginine methyltransferase / Protein Binding / Protein folding / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - immunology / Protein-Arginine N-Methyltransferases - antagonists & inhibitors / Protein-Arginine N-Methyltransferases - genetics / Protein-Arginine N-Methyltransferases - immunology / Science / Science (multidisciplinary) / Signal Transduction / Survival / X-Box Binding Protein 1 - antagonists & inhibitors / X-Box Binding Protein 1 - genetics / X-Box Binding Protein 1 - immunology / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation