Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
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- 1 February 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (2), 254-269
- https://doi.org/10.1158/2159-8290.cd-19-0672
Abstract
Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat BRAFV600E/K-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi–resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi–induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma. Significance: Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma. See related commentary by Smalley, p. 176. This article is highlighted in the In This Issue feature, p. 161Keywords
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Funding Information
- HHS | NIH | National Cancer Institute (CA196278)
- HHS | NIH | National Cancer Institute (CA160495)
- HHS | NIH | National Cancer Institute (CA182635)
- Dr. Ralph and Marian Falk Medical Research Trust (N/A)
- HHS | National Institutes of Health (AR055398)
- HHS | National Institutes of Health (AR074564)
- HHS | NIH | National Cancer Institute (CA207855)
- U.S. Department of Defense (PC150650)
- American Cancer Society (PF-18-096-01-LIB)
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