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AXL Is a Potential Target for Therapeutic Intervention in Breast Cancer Progression

Yi-Xiang Zhang¹, Peter G. Knyazev¹, Yuri V. Cheburkin¹, Kirti Sharma¹, Yuri P. Knyazev¹, László rfi^2,3, István Szabadkai³, Henrik Daub¹, György Kéri^2,3 and Axel Ullrich¹

¹ Max Planck Institute of Biochemistry, Martinsried, Germany; ² Semmelweis University and ³ Vichem Chemie Ltd., Budapest, Hungary

Requests for reprints: Axel Ullrich, Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, Germany. Phone: 49-89-85782512; E-mail: ullrich{at}biochem.mpg.de.

Key Words: AXL • Motility • Invasivity • 3-quinolinecarbonitrile • Breast Cancer

Protein kinases play important roles in tumor development and progression. A variety of members of this family of signal transduction enzymes serve as targets for therapeutic intervention in cancer. We have identified the receptor tyrosine kinase (RTK) AXL as a potential mediator of motility and invasivity of breast cancer cells. AXL is expressed in most highly invasive breast cancer cells, but not in breast cancer cells of low invasivity. Ectopic expression of AXL was sufficient to confer a highly invasive phenotype to weakly invasive MCF7 breast cancer cells. Experimental inhibition of AXL signaling by a dominant-negative AXL mutant, an antibody against the extracellular domain of AXL, or short hairpin RNA knockdown of AXL decreased motility and invasivity of highly invasive breast cancer cells. To selectively interfere with cancer cell properties defining the rate of disease progression, we identified 3-quinolinecarbonitrile compounds, which displayed potent inhibitory activity against AXL and showed strong interference with motility and invasivity of breast cancer cells. Our findings validated the RTK AXL as a critical element in the signaling network that governs motility and invasivity of breast cancer cells, and allowed the identification of experimental anti-AXL small molecular inhibitors that represent lead substances for the development of antimetastatic breast cancer therapy. [Cancer Res 2008;68(6):1905–15]