title: Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations.
abstract: Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. Eighty percent of UMs harbor mutations in the Gαq family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQ(Q209L)-transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model. Our data identify PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and demonstrate that combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.
authors.affiliation: 1] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis, Cambridge, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tan
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Porter
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Jager
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis, Cambridge, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Emery
authors.affiliation: 1] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004357:Drug Synergism; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D020128:Inhibitory Concentration 50; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D020125:Mutation, Missense; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C581313:binimetinib; C543528:sotrastaurin; D011493:Protein Kinase C; D020930:MAP Kinase Kinase Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11