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Updated: Dec 8, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Chloroquine Sensitizes GNAQ/11-mutated Melanoma to MEK1/2 Inhibition
Amanda Truong1,2, Jae Hyuk Yoo3, Michael T Scherzer1,2
1Department of Oncological Sciences, University of Utah, Salt Lake City, Utah.
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 autophagy or lysosome function resulted in enhanced cell death. Moreover, the combination of MEK1/2 inhibition, using trametinib, with the lysosome inhibitor, chloroquine, also increased cytotoxicity. Treatment of mice bearing GNAQ/11-driven melanomas with trametinib plus hydroxychloroquine resulted in inhibition of tumor growth and significantly prolonged survival. Interestingly, lysosomal- and autophagy-specific inhibition with bafilomycin A1 was not sufficient to promote cytotoxicity in combination with trametinib. However, the addition of YAP inhibition with trametinib plus bafilomycin A1 resulted in cell death at comparable levels to trametinib plus chloroquine (T/CQ) treatment. Furthermore, T/CQ-treated cells displayed decreased YAP nuclear localization and decreased YAP transcriptional activity. Expression of a constitutively active YAP5SA mutant conferred resistance to T/CQ-induced cell death.
Conclusions:
These results suggest that YAP, MEK1/2, and lysosome function are necessary and critical targets for the therapy of GNAQ/11-driven melanoma, and identify trametinib plus hydroxychloroquine as a potential treatment strategy for metastatic uveal melanoma.
Insights
Targeting MEK1/2 and lysosome function with trametinib and hydroxychloroquine shows promise for metastatic uveal melanoma. This combination therapy inhibits tumor growth and prolongs survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Uveal melanoma (UM) is frequently driven by GNAQ/11 mutations, activating oncogenic MAPK and YAP pathways.
- Current therapies for metastatic UM have shown limited efficacy.
Purpose of the Study:
- To investigate the efficacy of combining MAPK pathway inhibition with lysosome or autophagy inhibition in GNAQ/11-mutated uveal melanoma.
- To identify the mechanisms underlying the cytotoxicity of MEK1/2 inhibitor and chloroquine combination therapy.
Main Methods:
- In vitro and in vivo testing of MEK1/2 inhibitors (trametinib) combined with lysosome inhibitors (chloroquine, hydroxychloroquine) or autophagy inhibitors (bafilomycin A1).
- Assessment of cell death, tumor growth, and survival in preclinical models.
- Analysis of YAP pathway activity and localization.
Main Results:
- MEK1/2 inhibition induced autophagy; combined inhibition of GNAQ/11, autophagy, or lysosome function enhanced cell death.
- Trametinib plus hydroxychloroquine significantly inhibited tumor growth and prolonged survival in mice.
- YAP inhibition was crucial for trametinib plus bafilomycin A1-induced cell death, similar to trametinib plus chloroquine.
- Trametinib plus chloroquine treatment reduced YAP nuclear localization and transcriptional activity, with YAP mutations conferring resistance.
Conclusions:
- YAP, MEK1/2, and lysosome function are critical therapeutic targets in GNAQ/11-driven melanoma.
- Trametinib plus hydroxychloroquine represents a potential treatment strategy for metastatic uveal melanoma.
