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Additional file 2:Evidence of subclonal heterogeneity from RNA-Seq data across a collection of melanoma samples. Allelic imbalance along each gene demonstrates subclonal heterogeneity. The score of the non-reference nucleotide has been calculated as 0.5- | 0.5 - (#B/(#B+#A)) |, where #A and #B are the numbers of reads hosting the reference and non-reference nucleotide respectively. However, all the reported genes have a multimodal distribution of B-allele frequencies along at least one exon. The B-allele frequencies close to 0.5 have been marked in grey, B-alleles that significantly deviate from this cluster are considered acquired somatic mutations (black) and can be explained by subclonal heterogeneity. Vertical bars represent 95% confidence intervals. All non-reference nucleotides shown are supported by at least 100 reads. Vertical dashed lines mark the boundaries between exons in the transcript. (PDF 46 KB)

Additional file 1:Detecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies. Comparing the M-Measure-based approach to a state-of-the-art CNA algorithm by testing their ability to identify de novo aberrations in SNP-array signals from an evolving tumor at two time points. (DOC 820 KB)

Additional file of Detecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies

Additional file of Detecting copy number status and uncovering subclonal markers in heterogeneous tumor biopsies

The major drawback of melanoma therapy with BRAF and MAPK inhibitors is the innate and acquired drug resistance. We therefore explored alternative targets and developed a new compound, SAB298, that is a SRC-family kinase (SFK) inhibitor. The drug is cytotoxic to patient-derived melanoma cells regardless of oncogene expression and inhibits tumor growth in vivo. As expected, it inhibited SRC and PI3K activity, and had the additional property of ERBB2 inhibition, that lead to inactivation of the two ERK phosphatases PP2A and SHP2. In 57% of the melanoma cell lines tested, the consequent increase in ERK activity lead to proteolytic degradation of its substrate, the lineage specific transcription factor MITF, likely contributing to growth arrest. Treatment with a combination of SAB298 and AZD6244 (selumetinib), induced a synergistic growth inhibition, suggesting that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors.