Fig. 6

A Schematic diagram of how ERRα mediates the synthetic lethality effects of trametinib and simvastatin. Proposed working model: a EGF stimulation promotes ERRα expression, probably via the up-regulation of RAS-ERK signalling. Cholesterol serves as a natural ERRa agonist to increase ERRα transcriptional activity, thereby promoting colon cancer cell proliferation and tumour growth. b Trametinib inhibits ERRα expression, perhaps via directly down-regulating RAS-ERK signalling. A reduction in cholesterol synthesis by statins decreases ERRa transcriptional activity; therefore, trametinib combined with simvastatin effectively inhibits colon cancer cell proliferation and tumour growth