Figure 7.

Schematic presentation of the signaling pathways for tumor cell growth and the resistance mechanism proposed. Mutations in NRAS and BRAF lead to tumor cell growth through activating the MEK1/2-ERK pathway. LT and U0126 inhibit MEK1/2 and prevent tumor cell growth (solid box). However, the inhibition of MEK1/2 by LT or U0126 can lead to an HDAC8-dependent cell proliferation pathway that activates AKT through enhancing the PLCB1 expression in a low-DESC1 background (dotted box). The inhibition of HDAC8 can lead to the suppression of PLCB1 expression and induction of DESC1 expression, both of which cooperatively inhibit AKT activation and a resistance to MEK1/2 inhibition.