Figure 7. Schematic model illustrating the role of enhancer reprogramming in modulating sensitivity to MEK inhibitors in OV.

In sensitive cells (left), the negative regulators of the MAPK pathway, including SPRY2/4, DUSP6, and ETV4/5, are expressed with active enhancers. Trametinib constitutively inhibits ERK activity. In resistant cells (right), MAPK negative regulators are suppressed as a result of enhancer reprogramming from the active enhancer to the repressive enhancer, leading to relief of feedback inhibition of MAPK signaling and conferring trametinib resistance. HDAC inhibitors can attenuate the enhancer reprogramming and upregulate the negative regulators of the MAPK pathway, resulting in a more complete suppression of ERK activity and overcoming the resistance to trametinib.