Correlation between pre-existing MEK1^P124 mutations and clinical and in vitro response to BRAF inhibitors in metastatic melanoma.

9004 Background: MEK1 mutations can confer resistance to BRAF inhibitors although pre-existing MEK1P124 mutations do not preclude clinical responses to BRAF inhibitor therapy. We sought to determine if pre-existing MEK1P124 mutations affected clinical outcome in BRAF inhibitor treated melanoma. Methods: Data from three published data sets, and from patients treated at our institutions, were analyzed to determine if pre-existing MEKP124 mutations affect radiological response or progression-free survival (PFS) in BRAFV600 mutant metastatic melanoma patients treated with vemurafenib or dabrafenib. The effects of MEK1P124 mutations on MAPK pathway activity and response to dabrafenib were also investigated in a series of cell models. Results: 123 patients with pre-treatment tumors tested for MEK1 mutations were included. Those with a pretreatment MEKP124 mutation (n=12) had a poorer RECIST response (33% vs 71% CR or PR in MEK1P124 vs MEK1 wild-type, p=0.008), this was associated with a shorter median PFS in those with a MEK1P124 mutation (Median 3.1 vs 4.8 months, p=0.004). Introduction of MEK1 P124Q or P124S variants into BRAF-mutant SKMel28 melanoma cells resulted in diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival compared to cells ectopically expressing wild-type MEK1. The impact of MEK1P124-variants was significantly less than the effect of MEK1K57E, a known mechanism of acquired BRAF inhibitor resistance. Consistent with these data, two BRAF mutant cell lines with endogenous MEK1P124 mutations, including a short term culture generated pre-treatment from a patient who responded poorly to combined dabrafenib and trametinib, showed weak sensitivity to dabrafenib (IC50s 21 and 26nM) compared to a panel of MEK1 wild type/BRAF mutant cell lines (median IC50 7nM; range 4-14nM). In contrast, melanoma cell lines showed equivalent sensitivity to ERK inhibition, irrespective of the MEK1 genotype. Conclusions: Pre-existing MEKP124 mutations are associated with a reduced response to BRAF inhibitor therapy but are unlikely to affect response to ERK inhibitors.