fig6
![Resistance to ERK1/2 pathway inhibitors; sweet spots, fitness deficits and drug addiction](https://image.oaes.cc/357c9f43-0b5e-4e9d-8220-37330b7ee2d7/3093.fig.6.jpg)
Figure 6. LoVo cells acquire resistance to selumetinib through KRASG13D upregulation and mutation of MEK1. KRASG13D-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 MEK1G128D 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