fig1

Figure 1. COLO205 and HT29 cells acquire resistance to the MEKi selumetinib by amplifying their driving oncogene BRAF^V600E. COLO205 and HT29 colorectal cancer cells (both BRAF^V600E-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 BRAF^V600E (right). The consequent increase in BRAF^V600E 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