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Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
Journal article   Open access

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

Dan A Erkes, Weijia Cai, Ileine M Sanchez, Timothy J Purwin, Corey Rogers, Conroy O Field, Adam C Berger, Edward J Hartsough, Ulrich Rodeck, Emad S Alnemri, …
Cancer discovery, v 10(2), pp 254-269
Feb 2020
DOI: https://doi.org/10.1158/2159-8290.CD-19-0672
PMID: 31796433
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/2159-8290.cd-19-0672View
Published, Version of Record (VoR)CC BY V4.0,  Open
url
https://doi.org/10.1158/2159-8290.CD-19-0672View
Published, Version of Record (VoR) Open

Abstract

Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Cell Line, Tumor - transplantation Dendritic Cells - drug effects Dendritic Cells - immunology Disease Models, Animal Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Drug Resistance, Neoplasm - immunology Female Humans Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Male Melanoma - drug therapy Melanoma - genetics Melanoma - immunology Mice Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases - metabolism Mutation Proof of Concept Study Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Pyroptosis - drug effects Pyroptosis - genetics Pyroptosis - immunology Skin Neoplasms - drug therapy Skin Neoplasms - genetics Skin Neoplasms - immunology Tumor Microenvironment - drug effects Tumor Microenvironment - genetics Tumor Microenvironment - immunology ESI Highly Cited Paper (Incites)
Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat -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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341 citations in Scopus

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UN Sustainable Development Goals (SDGs)

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Highly Cited Paper 
Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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