Autophagy inhibition sensitizes targeted therapy-resistant melanoma to MEK1/2 inhibitors

Targeted therapy has dramatically improved the treatment landscape for metastatic melanoma, however is limited to those with BRAF(V600) mutations. GNAQ/GNA11 mutations are found in approximately 2% of melanoma, including 80% of uveal melanoma. Mutations in these G-alpha proteins lead to constitutive activation of multiple oncogenic pathways, including MAPK (RAF-->MEK1/2-->ERK1/2) signaling. Unfortunately, metastatic uveal melanoma is refractory to pharmacologic targeted therapies inhibiting MEK1/2, including trametinib and binimetinib. We showed that MEK1/2 inhibition increased autophagic flux in GNAQ/GNA11 mutated melanoma cell lines. The addition of autophagy inhibitors, such as chloroquine, resulted in synergistic cytotoxicity (Loewe model), demonstrating the cytoprotective role of autophagy as a result of MEK1/2 inhibitor treatment. Furthermore, combining trametinib with chloroquine or hydroxychloroquine resulted in a rapid and profound decrease in tumor burden in vivo compared to either treatment as monotherapy. This was also demonstrated in patient derived xenografts of NRAS-mutated cutaneous melanomas, a more common genetic subset of melanoma in which targeted therapy is also ineffective. Additionally, we showed that BRAF-mutated melanoma cell lines with genetically engineered or drug selected resistance to BRAF and MEK1/2 inhibitors displayed increased baseline autophagic flux, regardless of the presence of drug. The addition of autophagy inhibitors sensitized these resistant cells to BRAF and MEK1/2 inhibition. Our findings suggest a novel and potentially effective treatment strategy for melanomas with innate or acquired resistance to MEK1/2 inhibition.