Fig. 1.

Activation of PI3K by RAS mutations does not diminish sensitivity of melanoma cells to MEK inhibition. a Trametinib sensitivity data (IC₅₀ values) derived from the Genomics of Drug Sensitivity in Cancer database comparing BRAF^V600E-mutant and NRAS^Q61-mutant melanoma cell lines. Data highlighted in red indicate BRAF^V600E-mutant cells with concurrent loss of function NF1, PTEN mutations or the activating NRAS^Q61K mutation. The sensitivity of these cells (red points) were not significantly different from the other BRAF^V600E mutant melanoma cells (data highlighted in black, Mann–Whitney p = 0.410). Two-tailed Mann–Whitney test was used to determine differences between BRAF and NRAS mutant melanoma populations (p = 0.948). Median and interquartile ranges are shown on the scatter plot. b Heat map showing ssGSEA ratio scores of MAPK³², PI3K and mTORC signalling activity in 42 PROG melanomas relative to their matched PRE tumours. The main resistance mechanism is shown below each PROG tumour. Data are derived from^4,5,16,33 and tumour samples labelled according to¹⁶. DP single-drug (BRAF inhibitor) PROG tumours, DD-DP double-drug (combination BRAF and MEK inhibitor) PROG tumours. AMP BRAF amplification, splice BRAF-splice variant, - unknown mechanism of resistance