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

Sutton, SK; Carter, DR; Kim, P; Tan, O; Arndt, GM; Zhang, XD; Baell, J; Noll, BD; Wang, S; Kumar, N; McArthur, GA; Cheung, BB; Marshall, GM

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

Sutton, SK Carter, DR Kim, P Tan, O Arndt, GM Zhang, XD Baell, J Noll, BD Wang, S Kumar, N McArthur, GA Cheung, BB Marshall, GM

Permalink

Publisher:: IMPACT JOURNALS LLC
Publication Type:: Journal Article
Citation:: Oncotarget, 2016, 7, (32), pp. 52166-52178
Issue Date:: 2016-08-09

Closed Access

	Filename	Description	Size
	oncotarget-v7i32-10700.pdf	Published version	6.91 MB		View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Sutton, SK
dc.contributor.author	Carter, DR
dc.contributor.author	Kim, P
dc.contributor.author	Tan, O
dc.contributor.author	Arndt, GM
dc.contributor.author	Zhang, XD
dc.contributor.author	Baell, J
dc.contributor.author	Noll, BD
dc.contributor.author	Wang, S
dc.contributor.author	Kumar, N
dc.contributor.author	McArthur, GA
dc.contributor.author	Cheung, BB
dc.contributor.author	Marshall, GM
dc.date.accessioned	2022-08-11T02:10:48Z
dc.date.available	2016-05-29
dc.date.available	2022-08-11T02:10:48Z
dc.date.issued	2016-08-09
dc.identifier.citation	Oncotarget, 2016, 7, (32), pp. 52166-52178
dc.identifier.issn	1949-2553
dc.identifier.issn	1949-2553
dc.identifier.uri	http://hdl.handle.net/10453/159919
dc.description.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.
dc.format	Print
dc.language	eng
dc.publisher	IMPACT JOURNALS LLC
dc.relation.ispartof	Oncotarget
dc.relation.isbasedon	10.18632/oncotarget.10700
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Apoptosis
dc.subject.mesh	Benzimidazoles
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	DNA-Binding Proteins
dc.subject.mesh	Drug Screening Assays, Antitumor
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Humans
dc.subject.mesh	Indoles
dc.subject.mesh	Melanoma
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Rats
dc.subject.mesh	Rats, Wistar
dc.subject.mesh	Sulfonamides
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Tripartite Motif Proteins
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Vemurafenib
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred BALB C
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Nude
dc.subject.mesh	Rats
dc.subject.mesh	Rats, Wistar
dc.subject.mesh	Melanoma
dc.subject.mesh	Sulfonamides
dc.subject.mesh	Benzimidazoles
dc.subject.mesh	Indoles
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	DNA-Binding Proteins
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Antineoplastic Combined Chemotherapy Protocols
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Drug Screening Assays, Antitumor
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Proliferation
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Tripartite Motif Proteins
dc.subject.mesh	Vemurafenib
dc.title	A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner.
dc.type	Journal Article
utslib.citation.volume	7
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
dc.date.updated	2022-08-11T02:10:42Z
pubs.issue	32
pubs.publication-status	Published
pubs.volume	7
utslib.citation.issue	32

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/159919