Effect of dasatinib, a SRC kinase inhibitor, on lung cancer cells with defined epidermal growth factor receptor status

Abstract

3019 Background: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict sensitivity to small molecule inhibitors of EGFR such as gefitinib and erlotinib. Importantly, mutant EGFR selectively activates Akt and STAT pathways that are important in NSCLC cell survival. SRC-family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules such as PI3K/PTEN/Akt and STATs. Despite the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and SRC proteins, and evidence of elevated SRC activity in human lung cancers, the effect of SRC inhibition on cell fate is unknown. Methods: We evaluated the anti-tumor efficacy of a novel orally bioavailable SRC-ABL inhibitor dasatinib (BMS-354825) in non-small cell lung cancer cell lines with defined EGFR status including wildtype EGFR and mutant EGFR sensitive to gefitinib. Western blotting was used to evaluate the effect of dasatinib on downstream signaling pathways and in vitro assays were used to evaluate the effect cell cycle, apoptosis, and cell invasion. Results: Our results show that cell fate (death versus growth arrest) in lung cancer cells exposed to a SRC inhibitor is dependent on EGFR status. Dasatinib reduces mutant EGFR lung cancer cell viability through the induction of apoptosis and G1 cell cycle arrest while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of phosphorylated Akt and Stat3 survival proteins. In cell lines without EGFR mutation, dasatinib induces a G1 cell cycle arrest with associated changes in cyclin D and p27 proteins as well as inhibits activated FAK and prevents tumor cell invasion. Conclusions: Our results demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers through disruption of cell growth, survival and tumor invasion. Our results suggest EGFR status is critical in deciding cell fate in response to SRC inhibition. [Table: see text]