Poster Presentation 2014 Cutaneous Biology Meeting

HDAC inhibitors as a single or combination therapy in BRAF mutant melanoma (#24)

Danae M Sharp 1 2 , Kimberley A Beaumont 1 2 , Nikolas K Haass 1 3 4 , Stuart J Gallagher 5 , Wolfgang Weninger 1 3 6 , Peter Hersey 5 7
  1. Centenary Institute, Newtown, NSW, Australia
  2. Sydney Medical School, University of Sydney, NSW, Australia
  3. Discipline of Dermatology, University of Sydney, Camperdown, NSW, Australia
  4. Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia
  5. Kolling Institute of Medical Research, University of Sydney, NSW, Australia
  6. Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
  7. Melanoma Institute of Australia, North Sydney , NSW, Australia

Although selective BRAF inhibitors (BRAFi) have shown unprecedented clinical responses in patients with BRAF mutant metastatic melanoma, resistance is a major problem. Thus new therapeutic strategies that are able to treat BRAFi-resistant melanoma, or alternatively prevent BRAFi resistance, are needed. Histone deacetylase inhibitors (HDACi) are increasingly being investigated as a treatment option in multiple cancer types. In vitro data in melanoma indicated that HDACi are able to act synergistically with BRAFi to induce apoptosis. This combination therapy was effective in both BRAFi-naïve melanoma cell lines, derived from patients before exposure to the BRAFi, and in BRAFi-resistant melanoma cell lines derived from patients after development of resistance. In order to determine the effect of these drug combinations in vivo, we treated melanoma xenografts in NOD-SCID mice with panobinostat (HDACi) or/and LGX818 (selective BRAFi). Melanoma xenografts derived from BRAFi-naïve cells were susceptible to all drug regimens (single-agent HDACi or BRAFi or combination HDACi and BRAFi), with all treated tumours regressing over the course of a 21-day treatment regimen. The combination was not significantly better than single-agent BRAFi. However, after drug withdrawal there was a trend for slower tumour recurrence of the combination-treated tumours. While BRAFi-resistant xenografts responded significantly better to HDACi or combination compared to single-agent BRAFi, there was only a trend for the combination being superior to single-agent HDACi. Our in vivo data demonstrate that the HDACi is effective as a single agent in both BRAFi-naïve and resistant BRAF mutant melanoma. Although we could not demonstrate a significant synergy with the BRAFi in vivo, different dosing regimes or treatment schedules may reveal the synergy that has been seen in vitro. Further studies are needed to determine whether HDACi and BRAFi combination therapy would prevent or delay BRAFi resistance, and whether this combination would be superior to single-agent HDACi treatment in BRAFi-resistant tumours.