Abstract:
:Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Holland SJ,Pan A,Franci C,Hu Y,Chang B,Li W,Duan M,Torneros A,Yu J,Heckrodt TJ,Zhang J,Ding P,Apatira A,Chua J,Brandt R,Pine P,Goff D,Singh R,Payan DG,Hitoshi Ydoi
10.1158/0008-5472.CAN-09-2997subject
Has Abstractpub_date
2010-02-15 00:00:00pages
1544-54issue
4eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-2997journal_volume
70pub_type
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