Journal
CANCER RESEARCH
Volume 81, Issue 24, Pages 6233-6245Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-1547
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Funding
- National Science and Technology Major Project of China [2016ZX09101002]
- Guangdong Pearl River Talents Plan [2014ZT05Y232]
- Guangzhou Municipal Science and Technology Project [201909020004]
- Guangdong Basic and Applied Basic Research Foundation [2020B1515020054]
- Shenzhen Science and Technology Program grant [JCY20190807154813511]
- Fundamental Research Funds for the Central Universities [19ykpy144]
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BEBT-908, a dual PI3K/HDAC inhibitor, effectively inhibits tumor cell growth and enhances the efficacy of anti-PD1 therapy in mice by inducing immunogenic ferroptosis. It also promotes a proinflammatory tumor microenvironment and activates host antitumor immune responses, potentiating immune checkpoint blockade therapy. Mechanistically, BEBT-908-induced ferroptosis upregulates MHC class I and activates endogenous IFN gamma signaling in cancer cells via the STAT1 signaling pathway.
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 IFN gamma 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.
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