4.7 Article

Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis

Journal

CANCER DISCOVERY
Volume 10, Issue 2, Pages 254-269

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0672

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Funding

  1. NIH [R01 CA196278, R01 CA160495, R01 CA182635, AR055398, AR074564]
  2. Department of Defense [PC150650]
  3. Dr. Ralph and Marian Falk Medical Research Catalyst Trust Award
  4. National Cancer Center Support Grant [P30 CA056036]
  5. American Cancer Society CEOs Against Cancer PA Chapter Postdoctoral Fellowship [PF-18-096-01-LIB]
  6. [NIHK99 CA207855]

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Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA approved to treat BRAF(V600e/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.

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