title: Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells.
abstract: Blocking the migration of metastatic cancer cells is a major goal in the therapy of cancer. The receptor tyrosine kinase AXL is one of the main triggers for cancer cell migration in neoplasia of breast, colon, skin, thyroid and prostate. In our study we analyzed the effect of AXL inhibition on cell motility and viability in triple negative breast cancer cell lines overexpressing AXL. Thereby we reveal that the compound BMS777607, exhibiting the lowest IC50 values for inhibition of AXL kinase activity in the studied cell lines, attenuates cell motility to a lower extent than the kinase inhibitors MPCD84111 and SKI606. By analyzing the target kinases of MPCD84111 and SKI606 with kinase profiling assays we identified Lyn, a Src family kinase, as a target of both compounds. Knockdown of Lyn and the migration-related CRK-associated substrate (p130Cas), had a significant inhibitory effect on cell migration. Taken together, our findings highlight the importance of combinatorial or multikinase inhibition of non-receptor tyrosine kinases and AXL receptor tyrosine kinase in the therapy of triple negative breast cancer.
authors.affiliation: a Department of Molecular Biology; Max-Planck-Institute of Biochemistry ; Martinsried , Germany.
authors.forename: Kinga
authors.initials: K
authors.lastname: Pénzes
authors.forename: Christine
authors.initials: C
authors.lastname: Baumann
authors.forename: István
authors.initials: I
authors.lastname: Szabadkai
authors.forename: László
authors.initials: L
authors.lastname: Orfi
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Robert
authors.initials: R
authors.lastname: Torka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D050719:Crk-Associated Substrate Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D050719:Crk-Associated Substrate Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AKT, RAC-α serine/threonine-protein kinase; AXL; EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbant assay; FAK, focal adhesion kinase; Gas6, growth arrest specific 6; Lyn; MAPK, mitogen activated protein kinases; PI3K, phosphatidylinositol 3-kinase; Pyk2, proline-rich tyrosine kinase 2; RTK, receptor tyrosine kinase; TKI, tyrosine kinase inhibitor; TNBC, triple negative breast cancer; breast cancer; migration; migration related kinases; p130Cas; siRNA, short interfering RNA; tyrosine kinase inhibitors