title: Combined PKC and MEK inhibition for treating metastatic uveal melanoma.
abstract: Uveal melanoma (UM) is the most common primary intraocular malignancy and the second most common form of melanoma. UM has a strong tendency for metastatic disease, and no effective treatments have yet been identified. Activating oncogenic mutations are commonly found in GNAQ and GNA11 in UM, and inhibiting key downstream effectors of the GNAQ/11 signaling pathway represents a rational therapeutic approach for treating metastatic UM. Chen et al., doi:10.1038/onc.2013.418, now confirm activation of the MAPK and PKC pathways as a result of GNAQ and GNA11 activating mutations in melanocytes, and they demonstrate that MAPK activation occurs downstream of PKC activation. PKC inhibitors disrupt MAPK signaling and block proliferation of GNAQ/11 mutant UM cell lines and slow the in vivo growth of xenografted UM tumors without inducing their shrinkage. However, a combination of PKC and MEK inhibition led to sustained MAPK pathway inhibition and tumor regression in vivo. Hence, the authors concluded that MEK and PKC inhibition is synergistic, with superior efficacy to treatment of GNAQ/GNA11 mutant UMs with either drug alone.
authors.affiliation: Ocular Oncology Service, Moorfields Eye Hospital and St Bartholomew's Hospital and UCL Institute of Ophthalmology, London, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Sagoo
authors.affiliation: Ocular Oncology Service, Bascom Palmer Eye Institute & Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Harbour
authors.affiliation: Department of Oncology, Imperial College, Hammersmith Campus, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: National Heart and Lung Institute (NHLI), Imperial College of Science and Technology, London, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Bowcock
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D014604:Uveal Neoplasms / Q000188:drug therapy*
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11