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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• * Cancer cells, including ovarian cancer, utilize adaptive stress responses for survival.
• * The endoplasmic reticulum (ER) stress response, particularly the IRE1α/XBP1s pathway, is crucial for cancer cell adaptation.
• * CARM1 is overexpressed in ovarian cancer, presenting a potential therapeutic target.

Purpose of the Study:

• * To investigate the therapeutic potential of targeting the IRE1α/XBP1s pathway in CARM1-expressing ovarian cancer.
• * To elucidate the role of CARM1 in regulating the ER stress response and its interaction with XBP1s.
• * To evaluate the efficacy of IRE1α/XBP1s pathway inhibition alone and in combination with immune checkpoint blockade.

Main Methods:

• * In vitro and in vivo studies using ovarian cancer cell lines and xenograft models (orthotopic and patient-derived).
• * Investigation of CARM1's interaction with XBP1s during ER stress.
• * Assessment of IRE1α inhibitor B-I09 efficacy and synergy with anti-PD1 antibody in immunocompetent models.

Main Results:

• * CARM1-expressing ovarian cancer cells demonstrated selective sensitivity to IRE1α/XBP1s pathway inhibition.
• * CARM1 was found to regulate XBP1s target gene expression and directly interact with XBP1s.
• * IRE1α inhibition showed efficacy in CARM1-dependent ovarian cancer models in vitro and in vivo.
• * Combination therapy with an IRE1α inhibitor and anti-PD1 antibody showed synergistic effects in an immunocompetent model.

Conclusions:

• * Pharmacological inhibition of the IRE1α/XBP1s pathway is a promising therapeutic strategy for CARM1-expressing ovarian cancers.
• * Targeting the IRE1α/XBP1s pathway, potentially combined with immune checkpoint blockade, offers a novel treatment approach for CARM1-driven malignancies.