Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2007-02-01

AUTHORS

Richard S. Finn, Judy Dering, Charles Ginther, Cindy A. Wilson, Padraic Glaspy, Nishan Tchekmedyian, Dennis J. Slamon

ABSTRACT

Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-to-mesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 μM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40–59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (χ2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with “triple-negative” breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab). More... »

PAGES

319-326

Journal

TITLE

Breast Cancer Research and Treatment

ISSUE

3

VOLUME

105

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10549-006-9463-x

DOI

http://dx.doi.org/10.1007/s10549-006-9463-x

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1041402709

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17268817


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81 markers
82 mesenchymal transition
83 microarray
84 moesin
85 molecule inhibitors
86 potential predictive marker
87 potential role
88 predictive marker
89 profile
90 protein
91 protein 1
92 rationale
93 relationship
94 relative gene expression
95 relevant genes
96 response
97 role
98 scientific rationale
99 sensitivity
100 set
101 significant relationship
102 small molecule inhibitors
103 small molecule kinase inhibitors
104 specificity
105 subtypes
106 transition
107 treatment
108 treatment of women
109 vimentin
110 vitro 8
111 women
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