Limits...
Identification of candidate predictive and surrogate molecular markers for dasatinib in prostate cancer: rationale for patient selection and efficacy monitoring.

Wang XD, Reeves K, Luo FR, Xu LA, Lee F, Clark E, Huang F - Genome Biol. (2007)

Bottom Line: Ten genes, including that encoding urokinase-type plasminogen activator (uPA), were found to not only be potential efficacy markers but also to have reduced expression upon dasatinib treatment.Furthermore, EphA2, a target of dasatinib, was found to be a sensitivity biomarker.Using the gene expression profiling approach and preclinical models, we have identified prostatic biomarkers that are associated with sensitivity to dasatinib.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey, 08543, USA. xi-de.wang@bms.com

ABSTRACT

Background: Dasatinib is a potent, multi-targeted kinase inhibitor that was recently approved for treatment of chronic myelogenous leukemia resistant to imatinib. To aid the clinical development of dasatinib in prostate cancer, we utilized preclinical models to identify potential molecular markers for patient stratification and efficacy monitoring.

Results: Using gene expression profiling, we first identified 174 genes whose expression was highly correlated with in vitro sensitivity of 16 cell lines and, thus, considered as candidate efficacy predictive markers. Among these are important prostatic cell lineage markers, cytokeratin 5, androgen receptor and prostate specific antigen. Our results indicate that 'basal type' cell lines with high expression of cytokeratin 5 and low expression of androgen receptor or prostate specific antigen are sensitive to dasatinib. To identify markers as surrogates for biological activity, we treated cell lines with dasatinib and identified genes whose expression was significantly modulated by the drug. Ten genes, including that encoding urokinase-type plasminogen activator (uPA), were found to not only be potential efficacy markers but also to have reduced expression upon dasatinib treatment. The down-regulation of uPA by dasatinib was drug-specific and correlated with the sensitivity of cell lines to dasatinib. Furthermore, EphA2, a target of dasatinib, was found to be a sensitivity biomarker.

Conclusion: Using the gene expression profiling approach and preclinical models, we have identified prostatic biomarkers that are associated with sensitivity to dasatinib. This study has provided a basis for clinical evaluation of a potential dasatinib efficacy signature in prostate cancer.

Show MeSH

Related in: MedlinePlus

Correlation of EphA2 gene expression with sensitivity to dasatinib. (a) Negative correlation between the expression levels of EphA2 (black diamonds) and the IC50 (gray circles) values for the 16 cell lines. The coefficient of the Pearson correlation is -0.66, indicating a high reverse correlation. (b) Expression of EphA2 protein in five sensitive and three resistant cell lines. Overall, the protein expression levels in these cell lines correlated well with the mRNA levels detected by microarray analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2258199&req=5

Figure 2: Correlation of EphA2 gene expression with sensitivity to dasatinib. (a) Negative correlation between the expression levels of EphA2 (black diamonds) and the IC50 (gray circles) values for the 16 cell lines. The coefficient of the Pearson correlation is -0.66, indicating a high reverse correlation. (b) Expression of EphA2 protein in five sensitive and three resistant cell lines. Overall, the protein expression levels in these cell lines correlated well with the mRNA levels detected by microarray analysis.

Mentions: As shown in Figure 2a, the expression level of EphA2, as detected by microarray baseline profiling, was correlated with the IC50 values of the prostate cell lines (higher EphA2 expression with lower IC50 or high sensitivity, Pearson correlation coefficient = -0.66). As a validation, we also performed western blot analysis to examine the expression of EphA2 protein in five sensitive and three resistant cell lines (Figure 2b). Overall, those cell lines with higher levels of EphA2 mRNA expressed relatively higher levels of EphA2 protein, indicating good concordance between gene and protein expression for EphA2. While the EphA2 RNA level in DU145 cells was relatively low compared to the other sensitive cell lines, its protein level appeared comparable, suggesting that EphA2 expression is also regulated at the protein translation or stabilization levels. Our western blot results on EphA2 protein in PC3, DU145 and LNCaP cells are consistent with a previous report [14]. With the correlation of its expression with dasatinib sensitivity in cell lines, and being a target of the drug, EphA2 appears to be a strong candidate biomarker for dasatinib in prostate cancer.


Identification of candidate predictive and surrogate molecular markers for dasatinib in prostate cancer: rationale for patient selection and efficacy monitoring.

Wang XD, Reeves K, Luo FR, Xu LA, Lee F, Clark E, Huang F - Genome Biol. (2007)

Correlation of EphA2 gene expression with sensitivity to dasatinib. (a) Negative correlation between the expression levels of EphA2 (black diamonds) and the IC50 (gray circles) values for the 16 cell lines. The coefficient of the Pearson correlation is -0.66, indicating a high reverse correlation. (b) Expression of EphA2 protein in five sensitive and three resistant cell lines. Overall, the protein expression levels in these cell lines correlated well with the mRNA levels detected by microarray analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2258199&req=5

Figure 2: Correlation of EphA2 gene expression with sensitivity to dasatinib. (a) Negative correlation between the expression levels of EphA2 (black diamonds) and the IC50 (gray circles) values for the 16 cell lines. The coefficient of the Pearson correlation is -0.66, indicating a high reverse correlation. (b) Expression of EphA2 protein in five sensitive and three resistant cell lines. Overall, the protein expression levels in these cell lines correlated well with the mRNA levels detected by microarray analysis.
Mentions: As shown in Figure 2a, the expression level of EphA2, as detected by microarray baseline profiling, was correlated with the IC50 values of the prostate cell lines (higher EphA2 expression with lower IC50 or high sensitivity, Pearson correlation coefficient = -0.66). As a validation, we also performed western blot analysis to examine the expression of EphA2 protein in five sensitive and three resistant cell lines (Figure 2b). Overall, those cell lines with higher levels of EphA2 mRNA expressed relatively higher levels of EphA2 protein, indicating good concordance between gene and protein expression for EphA2. While the EphA2 RNA level in DU145 cells was relatively low compared to the other sensitive cell lines, its protein level appeared comparable, suggesting that EphA2 expression is also regulated at the protein translation or stabilization levels. Our western blot results on EphA2 protein in PC3, DU145 and LNCaP cells are consistent with a previous report [14]. With the correlation of its expression with dasatinib sensitivity in cell lines, and being a target of the drug, EphA2 appears to be a strong candidate biomarker for dasatinib in prostate cancer.

Bottom Line: Ten genes, including that encoding urokinase-type plasminogen activator (uPA), were found to not only be potential efficacy markers but also to have reduced expression upon dasatinib treatment.Furthermore, EphA2, a target of dasatinib, was found to be a sensitivity biomarker.Using the gene expression profiling approach and preclinical models, we have identified prostatic biomarkers that are associated with sensitivity to dasatinib.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey, 08543, USA. xi-de.wang@bms.com

ABSTRACT

Background: Dasatinib is a potent, multi-targeted kinase inhibitor that was recently approved for treatment of chronic myelogenous leukemia resistant to imatinib. To aid the clinical development of dasatinib in prostate cancer, we utilized preclinical models to identify potential molecular markers for patient stratification and efficacy monitoring.

Results: Using gene expression profiling, we first identified 174 genes whose expression was highly correlated with in vitro sensitivity of 16 cell lines and, thus, considered as candidate efficacy predictive markers. Among these are important prostatic cell lineage markers, cytokeratin 5, androgen receptor and prostate specific antigen. Our results indicate that 'basal type' cell lines with high expression of cytokeratin 5 and low expression of androgen receptor or prostate specific antigen are sensitive to dasatinib. To identify markers as surrogates for biological activity, we treated cell lines with dasatinib and identified genes whose expression was significantly modulated by the drug. Ten genes, including that encoding urokinase-type plasminogen activator (uPA), were found to not only be potential efficacy markers but also to have reduced expression upon dasatinib treatment. The down-regulation of uPA by dasatinib was drug-specific and correlated with the sensitivity of cell lines to dasatinib. Furthermore, EphA2, a target of dasatinib, was found to be a sensitivity biomarker.

Conclusion: Using the gene expression profiling approach and preclinical models, we have identified prostatic biomarkers that are associated with sensitivity to dasatinib. This study has provided a basis for clinical evaluation of a potential dasatinib efficacy signature in prostate cancer.

Show MeSH
Related in: MedlinePlus