期刊
FRONTIERS IN IMMUNOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.1005045
关键词
heat shock protein 90 (hsp90); isoform-selective inhibitor; immune checkpoint blockade (ICB); prostate cancer; breast cancer; CDK4; 6; interferon response; endogenous retrovirus
类别
资金
- Interdisciplinary Interface Training Program Grant from the Walther Cancer Foundation
- Harper Cancer Research Institute at University of Notre Dame
- National Institutes of Health [R01CA248033]
- Department of Defense CDMRP PCRP grants [W81XWH2010312, W81XWH2010332]
- Boler Family Foundation endowment at University of Notre Dame
- U.S. Department of Defense (DOD) [W81XWH2010312, W81XWH2010332] Funding Source: U.S. Department of Defense (DOD)
We developed a Hsp90 beta-selective inhibitor that is cytotoxic to cancer cells without inducing heat shock response. Our findings suggest that this Hsp90 beta inhibitor can significantly enhance the efficacy of ICB therapy and has good tolerability in mice.
Response resistance to the immune checkpoint blockade (ICB) immunotherapy remains a major clinical challenge that may be overcome through the rational combination of ICB and specific targeted therapeutics. One emerging combination strategy is based on sensitizing ICB-refractory tumors with antagonists of 90kD heat shock protein (Hsp90) that target all four isoforms. However, pan-Hsp90 inhibitors are limited by the modest efficacy, on-target and off-tumor toxicities, and induction of the heat shock response (HSR) that overrides the effect of Hsp90 inhibition. Recently, we developed Hsp90 beta-selective inhibitors that were cytotoxic to cancer cells but did not induce HSR in vitro. Here, we report that the Hsp90 beta inhibitor NDNB1182 downregulated CDK4 (an Hsp90 beta-dependent client protein) and induced the expression of endogenous retroviral elements and interferon-stimulated genes. In syngeneic mouse models of prostate cancer and breast cancer, NDNB1182 significantly augmented the efficacy of ICB therapy. Furthermore, NDNB1182 showed superior tolerability to the pan-Hsp90 inhibitor Ganetespib in mice. Our findings provide evidence that Hsp90 beta inhibition is a potentially effective and safe regimen to combine with ICB to treat immunotherapy-refractory solid tumors.
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