DOI: 10.5061/dryad.9gn07
title: Data from: Systems analysis of adaptive responses to MAP Kinase pathway blockade in BRAF mutant melanoma

description: 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.
description: SNP, insertion, and
 deletion calls made by GATK on panel of melanoma cell
 linesVCF file was generated
 using GATKmasterSnpCallsInDels.vcfSample ID and coverage stats tableTable contains columns for mapping cell lines to exome files, as well as average coverage and quantification of bases that had a Phred quality score of 20 or better.dbGaPStatsTable.txt1120AJM0001Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1120AJM0002Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1120AJM0003Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1316AJM0001Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1316AJM0002Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1371AJM0006Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1371AJM0007Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1371AJM0008Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1371AJM0009Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1371AJM0010Archive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1533AJM0004_bwaArchive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1533AJM0005_bwaArchive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1533AJM0006_bwaArchive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1533AJM0007_bwaArchive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1533AJM0008_bwaArchive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.1533AJM0009_bwaArchive of BAM files generated from exome sequencing of 16 melanoma cell lines. Exome sequences were generated using a combination of Agilent and NimbleGen captures. Variant calls as well as insertion and deletion calls were made using GATK.