Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571

Small cell lung cancer (SCLC) is an aggressive cancer characterized by seve ral autocrine growth mechanisms including stem cell factor and its receptor c-Kit, In order to arrive at potentially new and novel therapy for SCLC, w e have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not o nly inhibit cellular Abl tyrosine kinase activity but also the PDGF recepto r and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 m u M). There is no expression of the PDGF-receptor, and the Abl kinase is no t activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utili zing this preliminary data, we have determined that three (NCI-H69, NCI-H14 6 and NCI-H209) of five (including NCI-H82 and NCI-H249) SCLC cell lines ha d detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1-5 mu M of STI 571 after 48 h of treatment. The SCLC cell l ines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested betwee n 0.1-10 mu M) inhibition of tyrosine phosphorylation of c-git as well as i n vitro kinase activity (at 5 mu M) of c-Kit in response to STI 571, STI 57 1 inhibited cell motility, as assessed by time-lapsed video microscopy, wit hin 6 h of STI 571 treatment (5 mu M). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentratio n (5 mu M) that also inhibited cell growth. Cell cycle analysis of STI 571 responsive cells showed that cells were generally slowed in G2/M phase, but there was no arrest at G1/S, A downstream phosphorylation target of c-Kit, Akt, was not phosphorylated in response to stem cell factor in the presenc e of STI 571, These data imply that STI 571 inhibits growth of SCLC cells t hrough a mechanism that involves inactivation of the tyrosine kinase c-Kit, The effectiveness of STI 571 in this study suggests this drug may be usefu l in a clinical trial, for patients with SCLC.