Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

Abstract

B-RAF is the most frequently mutated protein kinase in human cancers.1 The finding that oncogenic mutations in BRAF are common in melanoma2 followed by the demonstration that these tumors are dependent on the RAF/MEK/ERK pathway3 offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts.4 Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032.5 In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumor regressions. At higher drug exposures afforded by a new amorphous drug formulation,4,5 greater than 80% inhibition of ERK phosphorylation in the tumors of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily.5 These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Initial attempts to block BRAF via non-RAF-isoform-selective inhibitors were unsuccessful 47 ; however, subsequent structure-guided drug-discovery efforts facilitated the development of clinically active BRAF inhibitors 48 . The first-in-class agent was vemurafenib, a selective inhibitor of V600-mutant BRAF.…”

The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation

“…Treatment with B-RAF selective inhibitors, such as vemurafenib or dabrafenib, has demonstrated significant benefit in melanoma patients with B-RAF V600E mutation, with extended patient progression-free survival and median overall survival compared with chemotherapy (3)(4)(5)(6). However, these responses were relatively short-lived, and drug resistance generally developed within 5 to 7 months (4,6).…”

Isolation of a Novel Thioflavin S–Derived Compound That Inhibits BAG-1–Mediated Protein Interactions and Targets BRAF Inhibitor–Resistant Cell Lines

“…This led to the development of small molecular weight inhibitors of RAF and MAP-ERK kinase (MEK; refs. 5,24), with recent clinical studies reporting that highly specific BRAF inhibitors are effective in the treatment of metastatic melanoma (25)(26)(27). However, initial promise has been hampered by the development of resistance (28)(29)(30), which is characterized by the reactivation of ERK1/2 (31)(32)(33) and has been attributed to various mechanisms including activating NRAS mutations (29), CRAF overexpression (34), compensatory upregulation of MAP2K kinase COT (28), activating MEK1 mutations (35), and amplification of mutant BRAF (36).…”