Abstract

Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF(V600E) melanoma. In AJCC stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease. In addition, dabrafenib and trametinib treatment of CD73(+) BRAF(V600E)-mutant melanomas caused profound CD73 downregulation in tumor cells. Inhibition of BRAF and MEK in combination with the A2A adenosine receptor provided significant protection against tumor initiation and metastasis formation in mice. Our results suggest that targeting adenosine may enhance therapeutic responses for melanoma patients receiving targeted or immune-based therapies. (C) 2017 AACR.

Authors	Young, Arabella; Ngiow, Shin Foong; Madore, Jason; Reinhardt, Julia; Landsberg, Jennifer; Chitsazan, Arash; Rautela, Jai; Bald, Tobias; Barkauskas, Deborah S.; Ahern, Elizabeth; Huntington, Nicholas D.; Schadendorf, Dirk; Long, Georgina V.; Boyle, Glen M.; Hoelzel, Michael; Scolyer, Richard A.; Smyth, Mark J.
Journal	CANCER RESEARCH
Pages	4684-4696
Volume	77
Date	1/09/2017
Grant ID	1078671
Funding Body	National Health and Medical Research Council of Australia (NHMRC) Senior Research Fellowship
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1158/0008-5472.CAN-17-0393
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