targeting cmet in melanoma mechanism of resistance and efficacy of novel combinatorial inhibitor therapy numerous tyrosine kinase inhibitors tkis targeting cmet are currently in clinical trials for several cancers their efficacy is limited due to the development of resistance the present study aims to elucidate this mechanism of cmet tki resistance by investigating key mtor and wnt signaling proteins in melanoma cell lines resistant to su11274 a cmet tki xenografts from ru melanoma cells treated with cmet tkis su11274 and jnj38877605 showed a 7 and 6fold reduction in tumor size respectively resistant cells displayed upregulation of phosphorylated cmet mtor p70s6kinase 4ebp1 erk lrp6 and active catenin in addition gata6 a wnt signaling regulator was upregulated and axin a negative regulator of the wnt pathway was downregulated in resistant cells modulation of these mtor and wnt pathway proteins was also prevented by combination treatment with su11274 everolimus an mtor inhibitor and xav939 a wnt inhibitor treatment with everolimus resulted in 56 growth inhibition and a triple combination of su11274 everolimus and xav939 resulted in 95 growth inhibition in ru cells the v600e braf mutation was found to be positive only in mu cells combination treatment with a cmet tki and a braf inhibitor displayed a synergistic effect in reducing mu cell viability these studies indicate activation of mtor and wnt signaling pathways in cmet tki resistant melanoma cells and suggest that concurrent targeting of cmet mtor and wnt pathways and braf may improve efficacy over traditional tki monotherapy in melanoma patients