1686P - Src inhibition as a method to overcome temozolomide resistance in melanoma

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Melanoma and other Skin Tumours
Translational Research
Presenter Emmet Jordan
Authors E.J. Jordan1, A. Eustace2, D.M. Collins2, N. O Donovan2, J.P. Crown3
  • 1Medical Oncology, Mater University Hospital, 01 - DUBLIN/IE
  • 2Dublin City University, N.I.C.B, DUBLIN/IE
  • 3Medical Oncology, St Vincents University Hospital, IE-4 - Dublin/IE

Abstract

Background

Malignant melanoma is resistant to chemotherapeutic agents. Src signalling plays a role in many malignancies including melanoma. Src is important in cell adhesion regulation, invasiveness and activating other downstream cellular pathways. Src activity is elevated in melanoma and has potential to provide a treatment target for melanoma. Temozolomide is an oral alkylating prodrug. Dasatinib is a dual Src/Abl kinase inhibitor with antiproliferative activity. AZD0530 is a selective oral Src kinase inhibitor.

Methods

We examined the anti-proliferative effects of dasatinib and AZD0530 alone and in combination with temozolomide (TMZ) in melanoma cell lines - MALME, HT144 parent and temozolomide resistant cell lines MALME-TMZ and HT144-TMZ. MALME-TMZ and HT144-TMZ were produced by the pulse method. IC50 and combination proliferation assays were performed using an acid phosphatase-based colourimetric assay.

Results

IC50 (50% inhibitory concentrations ± SD) values for TMZ were 338 ±25 µM in HTI44 and 490 ±19 µM in HT144-TMZ. IC50 values for TMZ were 306 ±29 µM in MALME and 515 ±45 µM in MALME-TMZ. Dasatinib was more effective as a single agent in HT144-TMZ (71 ± 8% growth inhibition at 1 µM) and MALME-TMZ (60 ± 6% growth inhibition at 1 µM) as compared to MALME (14 ± 10% inhibition at 1 µM) and HTI44 (0 ± 3% inhibition at 1 µM). The combination of dasatinib/TMZ was more effective than TMZ alone in HT144 and HT144-TMZ. AZD0530 increased proliferation in HT144 (25 ± 8% at 1 µM) and HT144-TMZ (35 ± 9% at 1 µM) as a single agent. AZD0530 caused growth inhibition as a single agent in MALME-TMZ (18 ± 6% inhibition at 1 µM) and MALME (4 ± 2% at 1 µM). The combination of AZD0530 and TMZ had no effect in HT144 or HT144-TMZ while AZD0530 combined with TMZ was more effective than TMZ alone in MALME and MALME-TMZ.

Conclusion

Dasatinib improved response to TMZ in both the chemotherapy naive and resistant cell line models tested (HT144, HT144-TMZ, MALME, MALME-TMZ). AZD0530 improved response to TMZ in one of the models only– MALME and MALME-TMZ. These in vitro results support further preclinical evaluation of Src Kinase inhibitors in combination with TMZ, and other DNA-targeting agents, particularly in TMZ-refractory melanoma.

Disclosure

All authors have declared no conflicts of interest.