Fifty percent of cutaneous
melanomas are driven by activated BRAFV600E, but
tumors treated with RAF inhibitors, even when they respond dramatically, rapidly adapt and develop resistance. Thus, there is a pressing need to identify the major mechanisms of intrinsic and adaptive resistance and develop
drug combinations that target these resistance mechanisms. In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant
melanoma cell lines of varying levels of resistance to
mitogen-activated protein kinase (MAPK) pathway inhibition, we identified the combination of
PLX4720, a targeted inhibitor of mutated BRaf, and
lapatinib, an inhibitor of the ErbB family of
receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to
PLX4720. To identify potential mechanisms of resistance to
PLX4720 treatment and synergy with
lapatinib treatment, we performed a multi-platform functional genomics analysis to profile the genome as well as the transcriptional and proteomic responses of these cell lines to treatment with
PLX4720. We found modest levels of resistance correlated with the zygosity of the BRAF V600E allele and
receptor tyrosine kinase (RTK) mutational status. Layered over base-line resistance was substantial upregulation of many ErbB pathway genes in response to BRaf inhibition, thus generating the vulnerability to combination with
lapatinib. The transcriptional responses of ErbB pathway genes are associated with a number of
transcription factors, including ETS2 and its associated cofactors that represent a convergent regulatory mechanism conferring synergistic drug susceptibility in the context of diverse mutational landscapes.