Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B-Raf, MEK, and Akt kinases.

Mitsiades N, Chew SA, He B, Riechardt AI, Karadedou T, Kotoula V, Poulaki V. "Invest Ophthalmol Vis Sci. 2011 Sep"

PURPOSE:

Inhibitors of B-Raf and MEK kinases maintain promise for your administration of cutaneous melanomas harboring BRAF mutations. BRAF mutations are uncommon in uveal melanomas (UMs), but somatic mutations inside the G protein α subunits Gαq and Gα11 (encoded by GNAQ and GNA11, respectively) happen within a mutually exclusive pattern in ～80% of UMs. The effect of B-Raf and MEK inhibitors on Gα-mutant UMs remains unidentified.

METHODS:

The effect with the B-Raf inhibitor PLX4720, the MEK inhibitor AZD6244, as well as the Akt inhibitors MK2206 on UM cell lines was assessed with the utilization of cell viability, proliferation, and apoptosis assays and immunoblot evaluation.

RESULTS:

BRAF-mutant UM cells were sensitive to each PLX4720 and AZD6244, undergoing cell cycle arrest although not apoptosis. UM cells having a Gα-protein mutation (GNAQ or GNA11) had been mildly delicate to AZD6244 but completely resistant to PLX4720. In reality, PLX4720 paradoxically increased ERK phosphorylation in Gα-mutant UM cells. The combination of AZD6244 with PLX4720 had synergistic anticancer exercise in BRAF-mutant cells although not in Gα-mutant cells. The Akt inhibitor MK2206 sensitized BRAF-mutant cells to both PLX4720 and AZD6244 and sensitized Gα-mutant cells to AZD6244 but didn't overcome the resistance from the Gα-mutant cells to PLX4720.

CONCLUSIONS:

The response of UM cells to inhibition of B-Raf, MEK, and Akt depends on their genotype. Future use of such targeted therapies in medical trials of UM individuals will demand careful style and individual choice based on genotype to provide personalised and powerful therapy.