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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.2.jpg)
Figure 2. MEKi withdrawal from BRAFV600E-amplified C6244-R cells causes p57KIP2-dependent G1 cell cycle arrest and ultimately reversal of MEKi-resistance. BRAFV600E 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 However, when selumetinib is withdrawn (middle), this enlarged pool of p-MEK1/2 is no longer restrained and levels of p-ERK1/2 increase to ~4-5 times those in parental cells.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 p57KIP2 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 BRAFV600E amplification in these revertant cells and a consequent re-setting of BRAF and p-ERK1/2 back to parental COLO205 levels. P: phosphate group