Abstract
Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi. BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi. Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma.See related commentary by Johnson and Dahlman, p. 6107.
Highlights
BRAF is a constituent of the MAPK signaling pathway and is one of the most commonly mutated oncogenes in human tumors [1].Note: Supplementary data for this article are available at Clinical Cancer Research Online.Ó2018 American Association for Cancer Research.The most prevalent BRAF mutations occur at codon V600, constitutively activating BRAF's kinase domain and enhancing MAPK signaling [2]
BRAF inhibitors (BRAFi) impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. Dual MAPK pathway inhibition (dMAPKi) was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma patientderived xenografts (PDX) with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases
Class II BRAF mutant melanoma is growth inhibited by dMAPKi
Summary
BRAF is a constituent of the MAPK signaling pathway and is one of the most commonly mutated oncogenes in human tumors [1].Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2018 American Association for Cancer Research.The most prevalent BRAF mutations occur at codon V600, constitutively activating BRAF's kinase domain and enhancing MAPK signaling [2]. BRAF is a constituent of the MAPK signaling pathway and is one of the most commonly mutated oncogenes in human tumors [1]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). The most prevalent BRAF mutations occur at codon V600, constitutively activating BRAF's kinase domain and enhancing MAPK signaling [2]. Given the importance of this hyperactivated pathway in cancer, several MAPK inhibitors have been developed for targeted treatment of V600 BRAF mutant tumors, including BRAF inhibitors (BRAFi; vemurafenib, dabrafenib, and encorafenib) and MEK inhibitors BRAFi and MEKi used as single agents, or in combination, have been shown to improve survival in BRAF V600 mutant melanoma and non–small cell lung cancer BRAFi and MEKi used as single agents, or in combination, have been shown to improve survival in BRAF V600 mutant melanoma and non–small cell lung cancer (NSCLC; refs. 4–6)
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