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, Glenn M. Marshall*

*Corresponding author for this work

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)52166-52178
Number of pages13
JournalOncotarget
Volume7
Issue number32
DOIs
Publication statusPublished - 9 Aug 2016
Externally publishedYes

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Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • BRAF inhibitor
  • Melanoma
  • Novel compound
  • TRIM16
  • Vemurafenib

Cite this

Sutton, S. K., Carter, D. R., Kim, P., Tan, O., Arndt, G. M., Zhang, X. D., ... Marshall, G. M. (2016). A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner. Oncotarget, 7(32), 52166-52178. https://doi.org/10.18632/oncotarget.10700