fig5

Figure 5. MEKi withdrawal from KRAS^G13D-amplified H6244-R cells does not result in defective cell proliferation, cell death or reversal of resistance, but promotes a ZEB1-dependent EMT. KRAS^G13D amplification activates an enlarged p-MEK1/2 pool that reinstates p-ERK1/2 in selumetinib-resistant HCT116 (H6244-R) cells to parental HCT116 levels in the presence of the MEKi selumetinib (top). This level of ERK1/2 activity maintains normal cell proliferation and survival. KRAS^G13D amplification in these cells also drives activation of PI3K-PKB signalling. When selumetinib is withdrawn (bottom), this enlarged pool of p-MEK1/2 is no longer restrained and levels of p-ERK1/2 increase to ~5-6 times those in parental cells. ERK1/2 hyperactivation following MEKi withdrawal did not inhibit cell proliferation or induce cell death, and selumetinib-resistance was stable even after prolonged periods of drug removal. However, ERK1/2 hyperactivation drives a ZEB1-dependent epithelial-to-mesenchymal transition (EMT) that confers resistance to classic chemotherapeutics (bottom). P: phosphate group; PIP₃: phosphatidylinositol-3,4,5-trisphosphate