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![Resistance to ERK1/2 pathway inhibitors; sweet spots, fitness deficits and drug addiction](https://image.oaes.cc/357c9f43-0b5e-4e9d-8220-37330b7ee2d7/3093.fig.1.jpg)
Figure 1. COLO205 and HT29 cells acquire resistance to the MEKi selumetinib by amplifying their driving oncogene BRAFV600E. COLO205 and HT29 colorectal cancer cells (both BRAFV600E-mutant) are addicted to ERK1/2 signalling (red) for proliferation and survival (left); inhibiting this pathway with the MEKi selumetinib halts cell proliferation and initiates cell death (middle). Selumetinib inhibits MEK1/2 by constraining the kinase domain catalytic sites in an inactive conformation, thereby inhibiting phosphorylation and activation of ERK1/2. However, selumetinib does not prevent phosphorylation of MEK1/2 by RAF (middle). Following 6-8 weeks culture in the presence of selumetinib, resistant derivatives of COLO205 (C6244-R) and HT29 (HT6244-R) cells emerge that proliferate normally and harbour amplification of BRAFV600E (right). The consequent increase in BRAFV600E expression results in 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 those in parental COLO205 or HT29 (right). P: phosphate group