Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors

dc.contributor.authorRahmy, Sharif
dc.contributor.authorMishra, Sanket J.
dc.contributor.authorMurphy, Sean
dc.contributor.authorBlagg, Brian S. J.
dc.contributor.authorLu, Xin
dc.contributor.departmentBiology, School of Science
dc.date.accessioned2024-06-05T17:43:22Z
dc.date.available2024-06-05T17:43:22Z
dc.date.issued2022-10-19
dc.description.abstractResponse 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.
dc.eprint.versionFinal published version
dc.identifier.citationRahmy, S., Mishra, S. J., Murphy, S., Blagg, B. S. J., & Lu, X. (2022). Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.1005045
dc.identifier.urihttps://hdl.handle.net/1805/41238
dc.language.isoen_US
dc.publisherFrontiers
dc.relation.isversionof10.3389/fimmu.2022.1005045
dc.relation.journalFrontiers in Immunology
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePublisher
dc.subjectheat shock protein 90 (hsp90)
dc.subjectisoform-selective inhibitor
dc.subjectimmune checkpoint blockade (ICB)
dc.subjectprostate cancer
dc.subjectbreast cancer
dc.subjectCDK4/6
dc.subjectinterferon response
dc.subjectendogenous retrovirus
dc.titleHsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors
dc.typeArticle
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