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. 2014 Mar 12;1(2):158-66.
doi: 10.18632/oncoscience.20. eCollection 2014.

Predictive biomarkers for dasatinib treatment in melanoma

Alex J Eustace  1 , Susan Kennedy  2 , Anne-Marie Larkin  1 , Thamir Mahgoub  3 , Dimitrios Tryfonopoulos  3 , Lorraine O'Driscoll  4 , Martin Clynes  1 , John Crown  3 , Norma O'Donovan  1
Affiliations

Predictive biomarkers for dasatinib treatment in melanoma

Alex J Eustace et al. Oncoscience. .

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.

Keywords: ANXA1; CAV-1; EphA2; Melanoma; biomarker; dasatinib.

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Figures

Figure 1
Figure 1. Percentage growth inhibition by dasatinib treatment for 5 days in a panel of melanoma cell lines
Figure 2
Figure 2. mRNA expression levels of ANXA1, CAV-1, EphA2, CAV-2, IGFBP2 and PTRF candidate markers measured by q-RT-PCR
Figure 3A
Figure 3A
Figure 4
Figure 4. Representative immunohistochemical staining of melanoma samples showing ANXA1, CAV-1, EphA2 and SRC kinase positive staining
See this image and copyright information in PMC

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