fig6

Figure 6. LoVo cells acquire resistance to selumetinib through KRAS^G13D upregulation and mutation of MEK1. KRAS^G13D-mutant LoVo colorectal cancer cells are addicted to ERK1/2 signalling (red) for proliferation and survival (top, left); inhibiting this pathway with the MEKi selumetinib halts cell proliferation and initiates cell death. Selumetinib inhibits MEK1/2 by constraining the kinase domain catalytic sites in an inactive conformation, thereby inhibiting phosphorylation and activation of ERK1/2 (top, right). Following 6-8 weeks culture in the presence of selumetinib, resistant derivatives of LoVo (L6244-R) cells emerge that proliferate normally and exhibit upregulation of KRAS expression and MEK1^G128D mutation (bottom). KRAS upregulation/MEK1 mutation result in activation of a larger pool of p-MEK1/2 with sufficient residual activity in the presence of selumetinib to reinstate ERK1/2 phosphorylation and pathway output to parental LoVo levels (bottom). P: phosphate group