Identification of a novel compound that synergistically inhibits cell growth with BRAF inhibitor in BRAF wildtype and NRAS mutant melanoma cells — ASN Events
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  3. Identification of a novel compound that synergistically inhibits cell growth with BRAF inhibitor in BRAF wildtype and NRAS mutant melanoma cells

Identification of a novel compound that synergistically inhibits cell growth with BRAF inhibitor in BRAF wildtype and NRAS mutant melanoma cells (#152)

Selina K Sutton 1 , Owen Tan 1 , Sonya Diakiw 1 , Greg Ardnt 1 , Ximing Du 2 , Hongyuan Yang 2 , Xu Dong Zhang 3 , Naresh Kumar 4 , Jonathan Baell 5 , Shudong Wang 6 , Belamy B Cheung 1 , Glenn M Marshall 1 7
  1. Children's Cancer Institute, Randwick, NSW, Australia
  2. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
  3. Priority Research Centre for Cancer Research Oncology and Immunology Unit, University of Newcastle, Newcastle, NSW, Australia
  4. School of Chemistry, University of New South Wales, Sydney, NSW, Australia
  5. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
  6. Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
  7. Kid's Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Australia

The discovery of BRAF inhibitors has revolutionized therapy for the 50% of patients with BRAFV600 mutant melanoma, however, BRAFWT melanomas have few effective therapies. The oncogene NRAS is activated by mutation in 15–20% of melanomas, but rarely concurrently with BRAF mutation. Clinically, single-agent MEK inhibition has had limited efficacy against NRAS mutant melanoma and BRAF inhibitor was not beneficial, highlighting the need for effective combination treatments.

    Among 24 ‘hit’ compounds from our recent drug screen for small molecules that enhanced the cytopathic effects of histone deacetylase inhibitors, we identified compound 012 (C-12), which unexpectedly had significant single agent activity on melanoma cell viability, with limited toxicity against normal human fibroblasts. Importantly, when combined with the BRAFV600 inhibitor, vemurafenib, C12 synergistically increased vemurafenib potency in 5 of 6 BRAFWT melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability (P<0.0001). Mechanistically, combination vemurafenib + C-12 markedly increased a growth suppressor, tripartite motif (TRIM) 16 protein level, and, knockdown of TRIM16 in melanoma cells significantly reduced vemurafenib + C-12 induced growth inhibition, suggesting that the combination exerted synergistic anti-cancer effects by inducing TRIM16 expression, resulting in consequent growth arrest. Microarray analysis revealed an increase in cholesterol biosynthesis suggestive of a response to decreased intracellular cholesterol with combination treatment. Synergy studies between cholesterol inhibitors, lovastatin & U18666A and vemurafenib revealed significant synergy preferentially targeting BRAFWT melanoma, in like manner to C-12. Taken together, we have identified a novel compound which works synergistically with BRAF inhibitor as an anti-cholesterol drug and specifically targets BRAFWT melanoma cells. We have further shown that statins combined with vemurafenib have significant anti-tumour activity in BRAFWT melanomas. Further elucidation of the mechanism of action may provide a means to overcome drug resistance for patients that have gained the NRAS mutation during vemurafenib treatment.