title: Predictive biomarkers for dasatinib treatment in melanoma.
abstract: Dasatinib has anti-proliferative and anti-invasive effects in melanoma cell lines. However clinical trials have shown modest activity for dasatinib in metastatic melanoma. Although dasatinib targets SRC kinase, neither expression nor phosphorylation of SRC appears to predict response to dasatinib. Identification of predictive biomarkers for dasatinib may facilitate selection of melanoma patients who are more likely to respond to dasatinib. We correlated the anti-proliferative effects of dasatinib in 8 melanoma cell lines with expression of a previously identified 6-gene biomarker panel. We examined the relationship between response to dasatinib and expression of each gene at both the mRNA and protein level. Dasatinib inhibited growth in 3 of the 8 cell lines tested. mRNA expression of the panel of 6 biomarkers did not correlate with response, whilst elevated protein expression of ANXA1, CAV-1 and EphA2 correlated significantly with response to dasatinib in the panel of cell lines. Expression of ANXA1, CAV-1 and EphA2 were analysed in 124 melanoma samples by immunohistochemistry. ANXA1 protein was detected in 81 % (97/120) of tumours, CAV-1 in 44 % (54/122) of tumours and EphA2 in 74 % (90/121) of tumours. Thirty one % (35/113) of tumours tested expressed all three markers and 19 % (21/112) had moderate or strong expression of ANXA1, CAV-1 and EphA2. Seventeen percent (19/112) of melanoma samples were positive for SRC kinase expression, combined with high expression of ANXA1, CAV-1 and EphA2. This subgroup may represent a population of melanoma patients who would be more likely to derive clinical benefit from dasatinib treatment.
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Eustace
authors.affiliation: Research Foundation, Royal Victoria Eye and Ear Foundation, Royal Victoria Eye and Ear Hospital.
authors.forename: Susan
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Larkin
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland ; Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: Thamir
authors.initials: T
authors.lastname: Mahgoub
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland ; Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tryfonopoulos
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Lorraine
authors.initials: L
authors.lastname: O'Driscoll
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Clynes
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland ; Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
authors.forename: Norma
authors.initials: N
authors.lastname: O'Donovan
keywords: ANXA1; CAV-1; EphA2; Melanoma; biomarker; dasatinib