Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

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-tomesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 lM 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 (v 2 = 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 ''triplenegative'' breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

“…We investigated the efficacy of the tyrosine kinase inhibitor dasatinib, currently in clinical use for the treatment of patients with refractory leukemias, as a single-agent in our preclinical assays. Although originally designed as a Src kinase family inhibitor, dasatinib appears to have broad tyrosine kinase specificity (43,45) and effectively inhibits breast tumor cell lines with the most aggressive phenotypes (41,42). Likewise, dasatinib suppressed each tumor cell line tested here including HER2Δ16-expressing trastuzumab-refractory tumor cell lines.…”

“…The tyrosine kinase inhibitor dasatinib has been recently approved for the treatment of patients with imatinib-refractory leukemias (39,40). Dasatinib is currently in clinical trials for the treatment of solid tumors and has recently been shown to inhibit the growth and proliferation of multiple breast tumor cell lines (41,42). Although originally designed as a Src kinase family inhibitor, dasatinib displays broader than anticipated tyrosine kinase inhibitor activity including direct inhibition of receptor tyrosine kinases (42)(43)(44)(45).…”

Src inhibitors in early breast cancer: a methodology, feasibility and variability study

“…Evidence also exists linking Src signaling to estrogen receptor signaling [9]. It is therefore possible that inhibition of Src could have an effect in tumors that fail to respond to hormone or growth factor therapies [10,11], a group where there remains a high level of unmet clinical need.…”

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

“…Dasatinib is used for the treatment of BCR-ABL-positive CML, resistant or intolerant to imatinib patients while it is also approved for Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia patients [12]. Dasatinib also demonstrated antitumoral activities on solid tumors such as prostate, breast, lung or head, and neck cancers [13][14][15][16].…”