Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.
Nat Commun. 2021 Sep 7;12(1):5321. doi: 10.1038/s41467-021-25684-3.
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.
CARM1 在包括卵巢癌在内的多种人类癌症中常常过表达。然而，基于 CARM1 表达的治疗方法仍然是一个未满足的需求。癌细胞通过激活 IRE1α/XBP1s 通路等途径来利用适应性反应，如内质网 (ER) 应激反应，从而存活下来。在这里，我们报告表达 CARM1 的卵巢癌细胞对 IRE1α/XBP1s 通路的抑制具有选择性敏感性。在 ER 应激反应中，CARM1 调节 XBP1s 靶基因的表达，并与 XBP1s 直接相互作用。IRE1α/XBP1s 通路的抑制在体外和体内的同源移植和患者来源的异种移植模型中均以 CARM1 依赖性的方式对卵巢癌有效。此外，IRE1α 抑制剂 B-I09 在表达 CARM1 的免疫功能健全的卵巢癌模型中与免疫检查点阻断抗 PD1 抗体具有协同作用。我们的数据表明，IRE1α/XBP1s 通路的药理学抑制单独或与免疫检查点阻断联合使用，代表了一种针对表达 CARM1 的癌症的治疗策略。
