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Predictive biomarkers for dasatinib treatment in melanoma
Alex J Eustace1, Susan Kennedy2, Anne-Marie Larkin1
1National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland.
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.
Insights
Dasatinib shows limited efficacy in metastatic melanoma. However, elevated protein levels of ANXA1, CAV-1, and EphA2 in melanoma tumors may predict response to dasatinib treatment, identifying patients likely to benefit.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Dasatinib exhibits anti-proliferative effects in melanoma cell lines, but clinical trials show modest activity in metastatic melanoma.
- SRC kinase is a target of dasatinib, yet its expression or phosphorylation does not predict treatment response.
- Identifying predictive biomarkers is crucial for selecting melanoma patients who will benefit from dasatinib therapy.
Purpose of the Study:
- To correlate the anti-proliferative effects of dasatinib with a 6-gene biomarker panel in melanoma cell lines.
- To investigate the relationship between dasatinib response and the mRNA and protein expression of these biomarkers.
- To evaluate the expression of ANXA1, CAV-1, and EphA2 in melanoma patient samples to identify potential predictive markers.
Main Methods:
- Assessed dasatinib's anti-proliferative effects on 8 melanoma cell lines.
- Correlated dasatinib response with mRNA and protein expression of a 6-gene biomarker panel.
- Analyzed ANXA1, CAV-1, and EphA2 protein expression in 124 melanoma tissue samples using immunohistochemistry.
Main Results:
- Dasatinib inhibited growth in 3 out of 8 melanoma cell lines.
- Elevated protein expression of ANXA1, CAV-1, and EphA2 significantly correlated with dasatinib response in cell lines, unlike mRNA expression.
- In melanoma samples, 81% expressed ANXA1, 44% CAV-1, and 74% EphA2. 19% of tumors showed moderate to strong expression of all three markers.
Conclusions:
- ANXA1, CAV-1, and EphA2 protein expression, but not mRNA, correlates with dasatinib's anti-proliferative effects in melanoma.
- A subgroup of melanoma patients with high expression of ANXA1, CAV-1, and EphA2 may benefit from dasatinib treatment.
- These three proteins represent potential predictive biomarkers for dasatinib therapy in metastatic melanoma.
