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

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.

• Authors: 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, Rugang Zhang
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 5321 (09 07 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34493732 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021. The Author(s).

Chemical References

• 4-methylumbelliferone 8-carbaldehyde
• Antibodies, Monoclonal
• Benzopyrans
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• X-Box Binding Protein 1
• XBP1 protein, human
• Hymecromone
• Protein-Arginine N-Methyltransferases
• coactivator-associated arginine methyltransferase 1
• ERN1 protein, human
• Protein Serine-Threonine Kinases
• Endoribonucleases

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Base Sequence
• Benzopyrans (pharmacology)
• Carcinoma, Ovarian Epithelial (genetics, immunology, pathology, therapy)
• Cell Line, Tumor
• Endoplasmic Reticulum Stress (drug effects)
• Endoribonucleases (antagonists & inhibitors, genetics, immunology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Hymecromone (analogs & derivatives, pharmacology)
• Immune Checkpoint Inhibitors
• Mice
• Molecular Targeted Therapy
• Ovarian Neoplasms (genetics, immunology, pathology, therapy)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, genetics, immunology)
• Protein Binding
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, immunology)
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors, genetics, immunology)
• Signal Transduction
• X-Box Binding Protein 1 (antagonists & inhibitors, genetics, immunology)
• Xenograft Model Antitumor Assays