Data from Preexisting MEK1<sup>P124</sup> Mutations Diminish Response to BRAF Inhibitors in Metastatic Melanoma Patients

<div>Abstract<p><b>Background:</b> MEK1 mutations in melanoma can confer resistance to BRAF inhibitors, although preexisting MEK1<sup>P124</sup> mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting MEK1<sup>P124</sup> mutations affected clinical outcome in BRAF inhibitor–treated patients with melanoma.</p><p><b>Methods:</b> Data from four published datasets were analyzed to determine whether preexisting MEK1<sup>P124</sup> mutations affect radiologic response or progression-free survival (PFS) in patients with BRAF<sup>V600</sup>-mutant metastatic melanoma treated with vemurafenib or dabrafenib. The effects of MEK1<sup>P124</sup> mutations on MAPK pathway activity and response to BRAF inhibition were also investigated in a series of cell models.</p><p><b>Results:</b> In a pooled analysis of 123 patients, the presence of a pretreatment MEK1<sup>P124</sup> mutation (<i>N</i> = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1<sup>P124Q/S</sup> vs. MEK1<sup>P124</sup> wild-type, <i>P</i> = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, <i>P</i> = 0.004). Furthermore, MEK1<sup>P124Q/S</sup> 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 MEK1<sup>P124</sup> mutations showed intermediate sensitivity to dabrafenib, but were highly sensitive to downstream inhibition of MEK or ERK.</p><p><b>Conclusion:</b> Taken together, our data indicate that preexisting MEK1<sup>P124</sup> 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. <i>Clin Cancer Res; 21(1); 98–105. ©2014 AACR</i>.</p></div>