MEK1/2-CDK4/6 targeting and resistance in melanoma cell lines

In this study, we evaluated combination schedules with intermittent dosing of MEKi and/or CDK4/6i in vivo in melanoma models to characterize mechanisms of acquired resistance that arise from each schedule. Our studies identify resistance to MEK1/2-CDK4/6 targeting associated with molecular alterations in NRAS and upregulation of ribosomal S6 protein (RPS6). These findings were supported by analysis of clinical trials samples. Targeting the resistance-associated pathway using mTOR inhibitors led to enhanced apoptosis in MEKi-CDK4/6i resistant cells and reduced tumor growth in vivo. Our findings provide new insight to scheduling and resistance to MEK1/2-CDK4/6 targeting and provide second-line treatment strategies for MEKi-CDK4/6i-resistant melanoma.