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

Dan A Erkes,Weijia Cai,Timothy J Purwin,Adam C Berger,Andrew E Aplin,Conroy O Field,Ileine M Sanchez,Corey Rogers,Emad S Alnemri,Ulrich Rodeck,Edward J Hartsough

doi:10.1158/2159-8290.cd-19-0672

Dan A Erkes, Weijia Cai + Show 9 more

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https://doi.org/10.1158/2159-8290.cd-19-0672

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Abstract

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.See related commentary by Smalley, p. 176.This article is highlighted in the In This Issue feature, p. 161.

Highlights

Melanoma represents a small fraction of cutaneous malignancies yet accounts for the majority of skin cancer–related mortalities [1]
Acquired resistance is often due to reactivation of the MEK–ERK1/2 pathway caused by mechanisms including NRAS mutation, increased BRAF copy number, and aberrant
We have recently shown that pyroptosis can be initiated by caspase-3–mediated gasdermin E (GSDME) cleavage in response to various apoptotic stimuli [32, 34]

Summary

Introduction

Melanoma represents a small fraction of cutaneous malignancies yet accounts for the majority of skin cancer–related mortalities [1]. Agents targeting the MEK–ERK1/2 pathway or immune checkpoints have emerged as effective treatment modalities that significantly improve progression-free survival and overall survival for patients with stage III and stage IV melanoma [2,3,4]. Targeted therapy elicits high response rates with the majority of patients with BRAFV600E/K-mutant melanoma exhibiting tumor shrinkage in response to the combination of BRAF and MEK inhibitors (BRAFi + MEKi). A limitation of targeted therapies is that tumors frequently recur within 13 months [5]. Acquired resistance is often due to reactivation of the MEK–ERK1/2 pathway caused by mechanisms including NRAS mutation, increased BRAF copy number, and aberrant. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

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