Data from: Systems analysis of adaptive responses to MAP Kinase pathway blockade in BRAF mutant melanoma

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.