Chloroquine Sensitizes GNAQ/11-mutated Melanoma to MEK1/2 Inhibition.

ABSTRACT:

Purpose

Mutational activation of GNAQ or GNA11 (GNAQ/11), detected in >90% of uveal melanomas, leads to constitutive activation of oncogenic pathways, including MAPK and YAP. To date, chemo- or pathway-targeted therapies, either alone or in combination, have proven ineffective in the treatment of patients with metastatic uveal melanoma.

Experimental design

We tested the efficacy of chloroquine or hydroxychloroquine, in combination with MAPK pathway inhibition in GNAQ/11-mutated cells in vitro and in vivo and identified mechanisms of MEK1/2 inhibitor plus chloroquine-induced cytotoxicity.

Results

Inhibition of GNAQ/11-mediated activation of MAPK signaling resulted in the induction of autophagy. Combined inhibition of Gα and aut

SUBMITTER: Truong A 

PROVIDER: S-EPMC7710560 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature