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.
SNP, insertion, and deletion calls made by GATK on panel of melanoma cell lines
VCF file was generated using GATK
masterSnpCallsInDels.vcf
Sample ID and coverage stats table
Table 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.txt
1120AJM0001
Archive 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.
1120AJM0002
Archive 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.
1120AJM0003
Archive 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.
1316AJM0001
Archive 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.
1316AJM0002
Archive 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.
1371AJM0006
Archive 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.
1371AJM0007
Archive 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.
1371AJM0008
Archive 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.
1371AJM0009
Archive 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.
1371AJM0010
Archive 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_bwa
Archive 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_bwa
Archive 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_bwa
Archive 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_bwa
Archive 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_bwa
Archive 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_bwa
Archive 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.