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Src family kinase activity is elevated in a number of human cancers including breast cancer. This increased activity has been associated with aggressive disease and poor prognosis. Src inhibitors are currently in clinical development with a number of trials currently assessing their activity in breast cancer. However, the results to date have been disappointing and a further evaluation of the preclinical effects of Src inhibitors is required to help establish whether these agents will be useful in the treatment of breast cancer. In this study we investigate the effects of dasatinib, which is a potent inhibitor of Src family kinases, on the initiation and development of breast cancer in a genetically engineered model of the disease. The mouse model utilized is driven by expression of activated ErbB-2 under the transcriptional control of its endogenous promoter coupled with conditional loss of Pten under the control of Cre recombinase expressed by the BLG promoter. We show that daily oral administration of dasatinib delays tumour onset and increases overall survival but does not inhibit the proliferation of established tumours. The striking difference between the dasatinib-treated group of tumours and the vehicle controls was the prominent squamous metaplasia that was seen in six out of 11 dasatinib-treated tumours. This was accompanied by a dramatic up-regulation of both E-cadherin and β-catenin and down-regulation of ErbB-2 in the dasatinib-treated tumours. Dasatinib also inhibited both the migration and the invasion of tumour-derived cell lines in vitro. Together these data support the argument that benefits of Src inhibitors may predominate in early or even pre-invasive disease., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Src is the cellular counterpart of the first identified viral oncogene v-Src. It forms part of a large family of nonreceptor tyrosine kinases that have been extensively studied over the last few decades. This has led to the realization that Src can regulate a number of signaling pathways that impact on the behavior of tumor cells, including proliferation, survival, migration, invasion, and angiogenesis. There are currently four Src inhibitors (dasatinib, saracatinib, bosutinib, and KX01) in clinical development, and although there is a plethora of information on their activity in preclinical models their clinical efficacy has been disappointing. Here we review the current status of the Src inhibitors and highlight the difficulties involved in assessing these therapeutics in the clinical setting. In the future it will be important to combine our knowledge of basic Src biology with the use of appropriate preclinical models to aid the design of clinical trials. Taking this integrated approach will hopefully help to realize the true potential of Src kinase inhibitors.