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

Abstract

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.1 page(s