Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells.
OBJECTIVE
Epithelial tumors, including non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), present clinical challenges. One potential target for systemic therapy is Src family nonreceptor tyrosine kinases, which are overexpressed in these tumors and induce pleiotropic effects, including increased proliferation, enhanced survival, stimulation of angiogenesis, and changes in motility. Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of these kinases at subnanomolar concentrations. Therefore, we tested the antitumor effects of this inhibitor in vitro to determine whether in vivo analyses were warranted.


METHODS
The antitumor effects of dasatinib on HNSCC and NSCLC cells were evaluated using assays to measure cell cycle progression, apoptosis, migration, and invasion. Western blotting was used to monitor its effects on cell signaling.


RESULTS
Dasatinib inhibited migration and invasion in all cell lines and induced cell cycle arrest (blocking the G1-S transition) and apoptosis in some lines. The effects on migration and invasion correlated with the inhibition of Src and downstream mediators of adhesion [e.g., focal adhesion kinase (FAK), p130, and paxillin], and the cell cycle effects and apoptosis correlated with the induction of p27 and the dephosphorylation of Rb. Dasatinib also induced morphologic changes that were consistent with an upstream role for Src in regulating focal adhesion complexes.


CONCLUSIONS
This study showed that Src inhibition in HNSCC and NSCLC has antitumor effects in vitro. This suggests that dasatinib would have therapeutic activity against these tumors. Clinical studies in these tumor types are warranted.
Johnson
Faye M
FM
Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA. fmjohns@mdanderson.org
Saigal
Babita
B
Talpaz
Moshe
M
Donato
Nicholas J
NJ
D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000494:pharmacology; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D016193:G1 Phase; D005840:Gentian Violet / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D007797:Laminin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011509:Proteoglycans / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014343:Trypan Blue / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D050719:Crk-Associated Substrate Protein; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D051419:Paxillin; D011509:Proteoglycans; D011743:Pyrimidines; D016160:Retinoblastoma Protein; D013844:Thiazoles; C059485:matrigel; D000255:Adenosine Triphosphate; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D014343:Trypan Blue; D005840:Gentian Violet; D000069439:Dasatinib