title: A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner.
abstract: There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease.
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.|School of Women's and Children's Health, University of New South Wales Australia, New South Wales, Australia.
authors.forename: Selina K
authors.initials: SK
authors.lastname: Sutton
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.|School of Women's and Children's Health, University of New South Wales Australia, New South Wales, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carter
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.|School of Women's and Children's Health, University of New South Wales Australia, New South Wales, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kim
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.
authors.forename: Owen
authors.initials: O
authors.lastname: Tan
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Arndt
authors.affiliation: Priority Research Centre for Cancer Research Oncology and Immunology Unit, University of Newcastle, New South Wales, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baell
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, South Australia, Australia.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Noll
authors.affiliation: Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, South Australia, Australia.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Chemistry, University of New South Wales Australia, New South Wales, Australia.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Translational Research Laboratory, Peter MacCallum Cancer Centre, Victoria, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.|School of Women's and Children's Health, University of New South Wales Australia, New South Wales, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Children's Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia.|School of Women's and Children's Health, University of New South Wales Australia, New South Wales, Australia.|Kids Cancer Centre, Sydney Children's Hospital, New South Wales, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000187:drug effects; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; C000625868:C012 compound; D004268:DNA-Binding Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D000077484:Vemurafenib; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: BRAF inhibitor; TRIM16; melanoma; novel compound; vemurafenib