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Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss

Hiscox, Stephen Edward, Barrett-Lee, Peter, Borley, Annabel Catherine and Nicholson, Robert Ian 2010. Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss. European Journal of Cancer 46 (12) , pp. 2187-2195. 10.1016/j.ejca.2010.04.012

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Abstract

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Src kinases; Aromatase inhibitor; Protein kinase inhibitor; Breast cancer; Bone resorption; Metastasis
Publisher: Elsevier
ISSN: 0959-8049
Last Modified: 19 Dec 2017 03:43
URI: http://orca-mwe.cf.ac.uk/id/eprint/24754

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