fig2

Figure 2. MEKi withdrawal from BRAF^V600E-amplified C6244-R cells causes p57^KIP2-dependent G1 cell cycle arrest and ultimately reversal of MEKi-resistance. BRAF^V600E amplification results in an enlarged p-MEK1/2 pool that reinstates p-ERK1/2 in selumetinib-resistant COLO205 (C6244-R) cells to parental COLO205 levels in the presence of the MEKi selumetinib (left). This level of ERK1/2 activity maintains normal cell proliferation and survival. However, when selumetinib is withdrawn (middle), this enlarged pool of p-MEK1/2 is no longer restrained and levels of p-ERK1/2 increase to ~4-5 times those in parental cells. This ERK1/2 hyperactivation drives p57^KIP2 expression, which inhibits the cell cycle at the G1 phase (middle), and ultimately selects for reversal of selumetinib resistance (revertant C6244-R(-), right). This reversal of MEKi resistance is due to loss of BRAF^V600E amplification in these revertant cells and a consequent re-setting of BRAF and p-ERK1/2 back to parental COLO205 levels. P: phosphate group