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

Abstract

Purpose: 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. Experimental Design: 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 G 1 -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.

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

“…The induction of cleaved PARP is consistent with other preclinical studies showing apoptotic effects of Src inhibitors in sarcoma (29), mesothelioma (30), squamous cell carcinoma (31), and pancreas cancer (13).…”

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

“…The current data from our group as well as data independently generated by Clark et al [20] indicate some dependence on src signaling pathways in the basal subgroup of breast Table 1 (R = resistant, M = moderately sensitive, S = highly sensitive) Table 3 Significant expression of one of the three genes moesin (MSN), caveolin-1 (CAV1), and yes-associated protein-1 (YAP1) above the reference is associated with response to dasatinib with a high sensitivity and specificity, 88% and 86%, respectively cancers in vitro. Other recent research has supported the role of src inhibition with dasatinib in head and neck, pancreatic and lung cancer models as well [38][39][40]. Finally, mutations in the abl kinase are the defining alteration in chronic myelogenous leukemia and have been the basis for molecular targeting of that disease initially with imatinib and now dasatinib.…”

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib

“…[28][29][30][31][32] However, the concentrations used in some of the studies were much higher than those used clinically in CML patients. 28,32 The use of high concentrations raises the concern of drug toxicity, as pleural effusion is a welldocumented side effect of dasatinib. 33 In the current study, we define sensitivity as IC 50 less than 128 nM.…”