Editors' ChoiceCancer

One target to quench many

Sci. Signal.  28 Jun 2016:
Vol. 9, Issue 434, pp. ec151
DOI: 10.1126/scisignal.aah4181

Uveal melanoma is a rare but aggressive cancer of the eye for which there are limited treatment options for the primary tumor and none for the metastatic form. Uveal melanomas frequently have activating mutations in GNAQ and GNA11, which encode Gαq and Gα11, respectively, two Gq members of the α subunit family of G protein–coupled receptor proteins. These Gαq proteins stimulate proliferative pathways mediated by diverse effectors, such as phospholipase C (PLC), the guanosine triphosphatase (GTPase) Rho, and the transcription factors β-catenin and YAP. These effectors can be pharmacologically targeted, but blocking one pathway still leaves the others intact. Yoo et al. found that activation of any of these pathways downstream of oncogenic GNAQ depended on a protein more proximal to Gαq proteins, which could also be targeted pharmacologically. Gαq proteins can activate or signal through the small GTPase ADP-ribosylation factor 6 (ARF6). The abundance of ARF6 was greater in human uveal melanomas that carried activating mutations in either GNAQ or GNA11 than in normal human choroid melanocytes. Knocking down GNAQ in GNAQ-mutant uveal melanoma cell lines reduced the activation (GTP-bound form) of ARF6. Knocking down ARF6 or GNAQ in either cell line caused similar reductions in cell proliferation and anchorage-independent colony growth, decreased the nuclear translocation of β-catenin, and decreased the activation of PLC, Rho, and downstream mediators and transcriptional effectors, including YAP. Expressing constitutively active ARF6 in GNAQ-deficient cells partially rescued cell proliferation, colony growth, and downstream pathway activity. Two guanine nucleotide exchange factors (GEFs), GEP100 and ARNO, mediate the GDP-GTP exchange (and hence activation) of ARF6. Knocking down GEP100 but not ARNO mimicked the cellular and molecular effects of GNAQ or ARF6 knockdown. Immunoprecipitation experiments revealed that GEP100 might form a complex with mutant GNAQ. Blocking ARF6 with the small-molecule inhibitor NAV-2729 reduced the proliferation of GNAQ-mutant uveal melanoma cells in culture and the growth of orthotopic xenograft tumors in mice. These findings identify a therapeutic target for uveal melanoma and potentially various other diseases that have activating mutations in Gα proteins.

J. H. Yoo, D. S. Shi, A. H. Grossmann, L. K. Sorensen, Z. Tong, T. M. Mleynek, A. Rogers, W. Zhu, J. R. Richards, J. M. Winter, J. Zhu, C. Dunn, A. Bajji, M. Shenderovich, A. L. Mueller, S. E. Woodman, J. W. Harbour, K. R. Thomas, S. J. Odelberg, K. Ostanin, D. Y. Li, ARF6 is an actionable node that orchestrates oncogenic GNAQ signaling in uveal melanoma. Cancer Cell 29, 889–904 (2016). [PubMed]

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