412P - Effects of statins on melanoma

Date 18 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Melanoma and other Skin Tumours
Presenter Khanh Tran
Citation Annals of Oncology (2016) 27 (suppl_9): ix126-ix129. 10.1093/annonc/mdw589
Authors K.B. Tran1, S. Kolekar2, S.M.F. Jamieson2, F.W. Hunter2, A. Jabed3, D. Li2, W.R. Wilson2, B.C. Baguley2, J.H. Shih3, C.M. Buchanan3, P.R. Shepherd3
  • 1Molecular Medicine And Pathology, University of Auckland Faculty of Medical & Health Sciences, 1703 - Auckland/NZ
  • 2Auckland Cancer Society Research Centre, University of Auckland Faculty of Medical & Health Sciences, 1023 - Auckland/NZ
  • 3Molecular Medicine And Pathology, University of Auckland Faculty of Medical & Health Sciences, 1023 - Auckland/NZ

Abstract

Background

HMG-CoA reductase inhibitors, better known as statins, were previously reported to have antitumor activity in a number of cancer types. However, the effects of statins in melanoma remain unclear.

Methods

A large panel of early passage melanoma cell lines representative of major driver mutations were prepared from biopsy samples from patients. Melanoma cells were treated in vitro with simvastatin, fluvastatin, or lovastatin, and analysed for proliferation, apoptosis induction, cell cycle progression, autophagy, and migration. Bisphosphonates were used to further investigate the involvement of the mevalonate pathway. The statins were then combined with current targeted drugs for in vitro treatment of melanoma cells, including mutant BRAF, MEK, PI3K, and mTOR inhibitors. A xenograft model was used to study the effect of statin in vivo. A novel approach using genome-scale CRISPR/Cas9 knockout screens (version 2 of the GeCKO library) was performed to study gene-related mechanisms.

Results

Data obtained in 45 melanoma cell lines demonstrated that all the three statins exhibited a strong inhibitory effect on the growth of melanoma cells at submicromolar concentrations in virtually all cell lines irrespective of genotype. Simvastatin induced apoptosis and autophagy, arrested cell cycle at G0/G1 phase, and inhibited cell migration. Analogous effects were also observed with other inhibitors of the mevalonate pathways. Importantly, we found that combinations of simvastatin or fluvastatin with vemurafenib, CI-1040, ZSTK474, or NVPBEZ-235 significantly enhanced the inhibitory effect toward melanoma cell growth in vitro. We further investigated the effects of simvastatin in vivo and found that simvastatin delayed the growth of NZM37 xenograft in athymic nude mice. Furthermore, we have completed whole-genome, positive-selection CRISPR screens with the three statins and demonstrated evolution of marked resistance to these agents. Analysis of enriched sgRNAs in these resistant cultures by next-generation sequencing is in progress.

Conclusions

These data suggest that statins have a strong anticancer activity against melanoma cells at submicromolar concentrations when used as monotherapy or in combination with current targeted treatment.

Clinical trial indentification

Legal entity responsible for the study

The University of Auckland

Funding

Cancer Society of New Zealand, Health Research Council, Maurice Wilkins Centre for Molecular Biodiscovery

Disclosure

All authors have declared no conflicts of interest.