A Dual PI3K/HDAC Inhibitor Induces Immunogenic Ferroptosis to Potentiate Cancer Immune Checkpoint Therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 24; pp. 6233 - 6245
• Main Authors: Fan, Fushun, Liu, Pei, Bao, Rudi, Chen, Jian, Zhou, Minhua, Mo, Zhenxian, Ma, Yaru, Liu, Haiqi, Zhou, Yiping, Cai, Xiong, Qian, Changgeng, Liu, Xinjian
• Format: Journal Article
• Language: English
• Published: United States 15.12.2021
• Subjects: Animals; Apoptosis; Cell Proliferation; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Ferroptosis; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-21-1547

The capacity of targeted anticancer agents to exert immunomodulatory effects provides a strong rationale to develop novel agents suitable for combinatorial regimens with immunotherapy to improve clinical outcomes. In this study, we developed a dual-targeting PI3K and HDAC inhibitor BEBT-908 that potently inhibits tumor cell growth and potentiates anti-PD1 therapy in mice by inducing immunogenic ferroptosis in cancer cells. Treatment with BEBT-908 promoted ferroptotic cell death of cancer cells by hyperacetylating p53 and facilitating the expression of ferroptotic signaling. Furthermore, BEBT-908 promoted a proinflammatory tumor microenvironment that activated host antitumor immune responses and potentiated immune checkpoint blockade therapy. Mechanistically, BEBT-908-induced ferroptosis led to upregulation of MHC class I and activation of endogenous IFNγ signaling in cancer cells via the STAT1 signaling pathway. The dual PI3K/HDAC inhibitor BEBT-908 is a promising targeted therapeutic agent against multiple cancer types that promotes immunogenic ferroptosis and enhances the efficacy of immunotherapy. SIGNIFICANCE: The dual PI3K/HDAC inhibitor BEBT-908 elicits potent antitumor responses, effectively inducing immunogenic ferroptosis of tumor cells and potentiating cancer immunotherapy.