Figure 6. Cartoon of EGFR-mediated signalling pathways and their regulation by NF1.

EGFR engages the MAPK and PI3K pathways in response to EGF ligand. NF1 negatively regulates RAS such that NF1 loss leads to activation of RAS. In DIFI cells, loss of NF1 results in moderate activation of the MAPK pathway but has no effect on the PI3K pathway. Combined inhibition of EGFR and MEK is synergistic in NF1-wildtype and NF1-targeted DIFI cells. However, SNUC4 and SNU1040 cells are less sensitive to EGFR/MEK inhibition and require inhibition of EGFR, MEK and PI3K. As observed in BRAF-mutant colorectal cancer, a triple combination of EGFR, MEK and PI3K inhibitors may warrant investigation in BRAF/KRAS/BRAF^V600-wildtype colorectal cancer.