Targeting the IRE1alpha/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Jianhuang Lin; Heng Liu; Takeshi Fukumoto; Joseph Zundell; Quingqing Yan; C. A. Tang; S. Wu; W. Zhou; D. Guo; S. Karakashev; Chi-Hang Anthony Hu; Kavitha Sarma; Andrew V. Kossenkov; Rugang Zhang

doi:10.1038/s41467-021-25684-3

Targeting the IRE1alpha/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Jianhuang Lin, Heng Liu, Takeshi Fukumoto, Joseph Zundell, Quingqing Yan, C. A. Tang, S. Wu, W. Zhou, D. Guo, S. Karakashev, Chi-Hang Anthony Hu, Kavitha Sarma, Andrew V. Kossenkov, Rugang Zhang

Nuclear Dynamics and Cancer (NDC)

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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 IRE1alpha/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1alpha/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1alpha/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, IRE1alpha 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 IRE1alpha/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

Original language	English
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25684-3
State	Published - 2021

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-25684-3

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title = "Targeting the IRE1alpha/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 IRE1alpha/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1alpha/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1alpha/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, IRE1alpha 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 IRE1alpha/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.",

keywords = "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",

author = "Jianhuang Lin and Heng Liu and Takeshi Fukumoto and Joseph Zundell and Quingqing Yan and Tang, {C. A.} and S. Wu and W. Zhou and D. Guo and S. Karakashev and Hu, {Chi-Hang Anthony} and Kavitha Sarma and Kossenkov, {Andrew V.} and Rugang Zhang",

note = "2041-1723 Lin, Jianhuang Orcid: 0000-0002-0035-0938 Liu, Heng Fukumoto, Takeshi Zundell, Joseph Yan, Qingqing Tang, Chih-Hang Anthony Wu, Shuai Orcid: 0000-0002-3183-5081 Zhou, Wei Guo, Dajiang Orcid: 0000-0001-5856-5854 Karakashev, Sergey Hu, Chih-Chi Andrew Orcid: 0000-0001-9024-2932 Sarma, Kavitha Kossenkov, Andrew V Zhang, Rugang Orcid: 0000-0002-7255-2360 K99 CA241395/CA/NCI NIH HHS/United States R01 CA163910/CA/NCI NIH HHS/United States R00 CA241395/CA/NCI NIH HHS/United States P01 AG031862/AG/NIA NIH HHS/United States P50 CA228991/CA/NCI NIH HHS/United States R50 CA211199/CA/NCI NIH HHS/United States R01 CA202919/CA/NCI NIH HHS/United States K23 NS105575/NS/NINDS NIH HHS/United States R01 CA239128/CA/NCI NIH HHS/United States F31 CA247336/CA/NCI NIH HHS/United States P30 CA010815/CA/NCI NIH HHS/United States R01 CA160331/CA/NCI NIH HHS/United States R01 CA163377/CA/NCI NIH HHS/United States DP2 NS105576/NS/NINDS NIH HHS/United States R01 CA190860/CA/NCI NIH HHS/United States 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. England 2021/09/09 Nat Commun. 2021 Sep 7;12(1):5321. doi: 10.1038/s41467-021-25684-3.",

year = "2021",

doi = "10.1038/s41467-021-25684-3",

language = "English",

volume = "12",

journal = "Nature Communications",

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TY - JOUR

T1 - Targeting the IRE1alpha/XBP1s pathway suppresses CARM1-expressing ovarian cancer

AU - Lin, Jianhuang

AU - Liu, Heng

AU - Fukumoto, Takeshi

AU - Zundell, Joseph

AU - Yan, Quingqing

AU - Tang, C. A.

AU - Wu, S.

AU - Zhou, W.

AU - Guo, D.

AU - Karakashev, S.

AU - Hu, Chi-Hang Anthony

AU - Sarma, Kavitha

AU - Kossenkov, Andrew V.

AU - Zhang, Rugang

N1 - 2041-1723 Lin, Jianhuang Orcid: 0000-0002-0035-0938 Liu, Heng Fukumoto, Takeshi Zundell, Joseph Yan, Qingqing Tang, Chih-Hang Anthony Wu, Shuai Orcid: 0000-0002-3183-5081 Zhou, Wei Guo, Dajiang Orcid: 0000-0001-5856-5854 Karakashev, Sergey Hu, Chih-Chi Andrew Orcid: 0000-0001-9024-2932 Sarma, Kavitha Kossenkov, Andrew V Zhang, Rugang Orcid: 0000-0002-7255-2360 K99 CA241395/CA/NCI NIH HHS/United States R01 CA163910/CA/NCI NIH HHS/United States R00 CA241395/CA/NCI NIH HHS/United States P01 AG031862/AG/NIA NIH HHS/United States P50 CA228991/CA/NCI NIH HHS/United States R50 CA211199/CA/NCI NIH HHS/United States R01 CA202919/CA/NCI NIH HHS/United States K23 NS105575/NS/NINDS NIH HHS/United States R01 CA239128/CA/NCI NIH HHS/United States F31 CA247336/CA/NCI NIH HHS/United States P30 CA010815/CA/NCI NIH HHS/United States R01 CA160331/CA/NCI NIH HHS/United States R01 CA163377/CA/NCI NIH HHS/United States DP2 NS105576/NS/NINDS NIH HHS/United States R01 CA190860/CA/NCI NIH HHS/United States 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. England 2021/09/09 Nat Commun. 2021 Sep 7;12(1):5321. doi: 10.1038/s41467-021-25684-3.

PY - 2021

Y1 - 2021

N2 - 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 IRE1alpha/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1alpha/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1alpha/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, IRE1alpha 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 IRE1alpha/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

AB - 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 IRE1alpha/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1alpha/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1alpha/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, IRE1alpha 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 IRE1alpha/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

KW - 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/ge

U2 - 10.1038/s41467-021-25684-3

DO - 10.1038/s41467-021-25684-3

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Targeting the IRE1alpha/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Abstract

Keywords

UN SDGs

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