Preexisting MEK1P124 Mutations Diminish Response to BRAF Inhibitors in Metastatic Melanoma Patients

Background: MEK1 mutations in melanoma can confer resistance to BRAF inhibitors, although preexisting MEK1(P124) mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting MEK1P124 mutations affected clinical outcome in BRAF inhibitor-treated patients with melanoma. Methods: Data from four published datasets were analyzed to determine whether preexisting MEK1P124 mutations affect radiologic response or progression-free survival (PFS) in patients with BRAF(V600)-mutant metastatic melanoma treated with vemurafenib or dabrafenib. The effects of MEK1P124 mutations on MAPK pathway activity and response to BRAF inhibition were also investigated in a series of cell models. Results: In a pooled analysis of 123 patients, the presence of a pretreatment MEK1P124 mutation (N -12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1(P124Q/) S vs. MEK1P124 wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004). Furthermore, MEK1P124Q/ S mutations were shown to have independent kinase activity and introduction of these mutations into a BRAF-mutant melanoma cell line diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival in the presence of dabrafenib compared with cells ectopically expressing wild-type MEK1. Consistent with these data, two BRAF-mutant cell lines with endogenous MEK1P124 mutations showed intermediate sensitivity to dabrafenib, but were highly sensitive to downstream inhibition of MEK or ERK. Conclusion: Taken together, our data indicate that preexistingMEK1P124 mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies involving MEK or ERK inhibitors.