Research Papers:

A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner

Selina K. Sutton, Daniel R. Carter, Patrick Kim, Owen Tan, Greg M. Arndt, Xu Dong Zhang, Jonathan Baell, Benjamin D. Noll, Shudong Wang, Naresh Kumar, Grant A. McArthur, Belamy B. Cheung and Glenn M. Marshall _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:52166-52178. https://doi.org/10.18632/oncotarget.10700

Metrics: PDF 2282 views  |   HTML 4435 views  |   ?  


Selina K. Sutton1,2, Daniel R. Carter1,2, Patrick Kim1,2, Owen Tan1, Greg M. Arndt1, Xu Dong Zhang3, Jonathan Baell4, Benjamin D. Noll5, Shudong Wang5, Naresh Kumar6, Grant A. McArthur7, Belamy B. Cheung1,2, Glenn M. Marshall1,2,8

1Children’s Cancer Institute for Medical Research, Lowy Cancer Research Centre, University of New South Wales, New South Wales, Australia

2School of Women’s and Children’s Health, UNSW Australia, New South Wales, Australia

3Priority Research Centre for Cancer Research Oncology and Immunology Unit, University of Newcastle, New South Wales, Australia

4Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia

5Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, South Australia, Australia

6School of Chemistry, University of New South Wales Australia, New South Wales, Australia

7Translational Research Laboratory, Peter MacCallum Cancer Centre, Victoria, Australia

8Kids Cancer Centre, Sydney Children’s Hospital, New South Wales, Australia

Correspondence to:

Glenn M. Marshall, email: [email protected]

Belamy B. Cheung, email: [email protected]

Keywords: BRAF inhibitor, melanoma, TRIM16, vemurafenib, novel compound

Received: April 30, 2016     Accepted: May 29, 2016     Published: July 19, 2016


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 10700