Rahmy, SharifMishra, Sanket J.Murphy, SeanBlagg, Brian S. J.Lu, Xin2024-06-052024-06-052022-10-20Rahmy S, Mishra SJ, Murphy S, Blagg BSJ, Lu X. Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors. Front Immunol. 2022;13:1005045. Published 2022 Oct 20. doi:10.3389/fimmu.2022.1005045https://hdl.handle.net/1805/41230Response 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 Hsp90β-selective inhibitors that were cytotoxic to cancer cells but did not induce HSR in vitro. Here, we report that the Hsp90β inhibitor NDNB1182 downregulated CDK4 (an Hsp90β-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 Hsp90β inhibition is a potentially effective and safe regimen to combine with ICB to treat immunotherapy-refractory solid tumors.en-USAttribution 4.0 InternationalHeat shock protein 90 (hsp90)Isoform-selective inhibitorImmune checkpoint blockade (ICB)Prostate cancerBreast cancerCDK4/6Interferon responseEndogenous retrovirusArticle