Fig. 8

MEKi + SRCi were predicted to occur predominantly in the KRAS-mutant, CMS4 CRCs. (a) Spearman correlation analysis of the 13-gene MEKi bypass vs. SRC activation signature scores in Moffitt 2012 CMS1-4 CRCs. (b) Scatter plots of 13-gene MEKi bypass vs. SRC activation scores are shown in CMS1 (n = 305), CMS2 (n = 675), CMS3 (n = 347) and CMS4 (n = 685), respectively, which clearly illustrate that CMS4 CRCs were preferentially associated with both higher 13-gene MEKi bypass and higher SRC activation scores (see the “CMS4” panel, the “right and upper” quadrant). (c) The 18-gene MEK activation versus the 5-gene Dasa-S signature scores were plotted in each of the CMS1-4 subtypes (n = 422 Moffitt CRC tumors with the mutation status of KRAS/NRAS/BRAF). BRAF (V600E) (blue); MUT KRAS/NRAS (red); WT RAS/RAF (gray). The 18-gene MEK activation versus the 5-gene Dasa-S signature scores were plotted in each of the CMS1-4 subtypes in (d) Marisa 458 CMS1-4 CRC tumors with MUT and WT KRAS/BRAF data and (e) Medico 113 CMS1-4 CRC cell lines with MUT and WT KRAS/BRAF data. These data suggest problematic RAS-mutant CMS4 stem-like tumors may be sensitive to the novel drug combination of a SRCi + MEKi. f. A proposed model illustrates a central role of SRC in mediating resistance to MEK inhibition in mesenchymal-like cancer stem cells. SRC may serve as a common targetable node, suggesting potential for a new biomarker-driven (MEKi + SRCi) drug combination targeting problematic SRC-mediated, mesenchymal CSCs, especially KRAS-mutant CMS4 CRCs