Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis.
Dan A ErkesWeijia CaiIleine M SanchezTimothy J PurwinCorey RogersConroy O FieldAdam C BergerEdward J HartsoughUlrich RodeckEmad S AlnemriAndrew E AplinPublished in: Cancer discovery (2019)
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.
Keyphrases
- cell death
- skin cancer
- wild type
- dendritic cells
- healthcare
- nlrp inflammasome
- immune response
- stem cells
- cancer therapy
- basal cell carcinoma
- cell cycle arrest
- machine learning
- quality improvement
- drug delivery
- inflammatory response
- diabetic rats
- emergency department
- bone marrow
- papillary thyroid
- drug induced
- high glucose
- metastatic colorectal cancer
- replacement therapy
- signaling pathway
- lymph node metastasis
- adverse drug
- squamous cell
- pain management
- drug administration