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

Abstract

Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit. In order to arrive at potentially new and novel therapy for SCLC, we have investigated the eects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not only inhibit cellular Abl tyrosine kinase activity but also the PDGF receptor and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 mM). There is no expression of the PDGF-receptor, and the Abl kinase is not activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utilizing this preliminary data, we have determined that three (NCI-H69, NCI-H146 and NCI-H209) of ®ve (including NCI-H82 and NCI-H249) SCLC cell lines had detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1 ± 5 mM of STI 571 after 48 h of treatment. The SCLC cell lines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested between 0.1 ± 10 mM) inhibition of tyrosine phosphorylation of c-Kit as well as in vitro kinase activity (at 5 mM) of c-Kit in response to STI 571. STI 571 inhibited cell motility, as assessed by timelapsed video microscopy, within 6 h of STI 571 treatment (5 mM). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentration (5 mM) 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 presence of STI 571. These data imply that STI 571 inhibits growth of SCLC cells through a mechanism that involves inactivation of the tyrosine kinase c-Kit. The eectiveness of STI 571 in this study suggests this drug may be useful in a clinical trial, for patients with SCLC. Oncogene (2000) 19, 3521 ± 3528.

Expression of the tyrosine kinase c‐kit is an independent prognostic factor in patients with small cell lung cancer

“…19 Based on these results, the growth-inhibitory effects of imatinib on c-kit ϩ cell lines have been examined by different groups. Treatment of SCLC cells with imatinib in vitro resulted in dose-dependent inhibition of proliferation of 10 -50% at a concentration of 1 M. 20,21 These in vitro data are promising, though the possible potential of imatinib for patients with c-kit ϩ SCLC remains unclear. The therapeutic effect is certainly dependent on c-kit mutations and the expression level of c-kit during therapy.…”

Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

“…19 c-Kit expression has been shown to control the growth of various cell lines, including gastrointestinal stromal tumors (GIST), hematopoietic cells, small cell lung cancer, and colorectal cancer. [20][21][22][23] Gain-of-function mutations in the KIT protein are found in various highly malignant human cancers, especially GIST. Gleevec (imatinib mesylate), a small molecule antagonist originally developed to treat chronic myelogenous leukemia (CML), acts by maintaining the bcr-abl kinase in an inactive conformation.…”

Expression of c-kit in fibroepithelial lesions of the breast is a mast cell phenomenon

“…2,5,6 C-kit has been implicated in the tumorigenesis of a variety of neoplasms including gastrointestinal stromal tumors (GISTs), small cell lung carcinomas, melanoma, and breast carcinoma. [7][8][9] Imatinib mesylate (Glivec internationally, Gleevec in the United States) 10,11 is a tyrosine kinase inhibitor and is used to treat GISTs that express ckit. 12 In 5-10% of GISTs that are c-kit mutation negative, mutations in another gene, platelet-derived growth receptor-a (PDGFRa; exons 12, 14, and 18), have been identified.…”