Recent advances in molecular understanding of pathogenesis of non-small cell lung cancer (NSCLC) at molecular level improved treatment outcome. However, the overall 5 year survival rate of individuals with lung cancer remains at < 15%. Therefore, novel therapeutic strategies are still needed to improve the survival rate of lung cancer patients. MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is involved in mediating tumorigenesis, cell motility, invasion and metastasis and is frequently deregulated in various human cancers including NSCLC. The MET receptor is an attractive potential target for novel therapeutic inhibition in human cancer. Recently, the MET tyrosine kinase inhibitors (TKIs), such as PHA-665752 and SU11274, have been most extensively evaluated in preclinical model, and have been known to be effective in growth inhibition of various malignancies. However, the mechanisms of MET TKIs on the growth-inhibitory effect on cancers are not clear. There have been a few reports that MET-induced oncogensis was accelerated by the loss of wild-type p53. In this study, we investigated the role of p53 in growth-inhibitory effects of MET TKI (SU11274) in the NSCLC cells. We used A549 cells (p53 wild-type) and Calu-1 cells (p53 null-type) and these cells were known to have wild-type MET. SU11274 showed more profound growth inhibition and apoptosis in A549 cells than in Calu-1 cells. The expression of p53 protein by modulation of p53 transitional level was observed by SU11274 treatment in A549 cells. Accumulated p53 protein after SU11274 treatment induced up-regulation of Bax, PUMA proteins and down-regulation of Bcl-2 protein and subsequently the activation of caspase 3 in p53 wild type A549 cells only. Inhibition of p53 expression using siRNA technology in A549 cells caused significant decrease of apoptosis by SU11274 and inactivation of p53-mediated apoptosis. The introduction of p53 into Calu-1 effectively leaded to SU11274-induced apoptosis through p53-mediated pathway. As same as in A549 cells to confirm the anti-tumor effect of SU11274 in vivo, A549 xenograft model was used and SU11274 effectively shrunk the tumor volume and also induced apoptosis via the increases of p53 protein. Taken together, SU11274 significantly induced apoptosis in wild-type p53 NSCLC cells through the increased expression p53-mediated apoptotic pathway but not in the p53-null NSCLC cells. These results suggest that p53 play an important role in SU11274-induced apoptosis and p53 status might be related with the sensitivity of SU11274 in NSCLC.

* This study was supported by a grant of the Korea Health 21 R&D project, the Ministry of Health & Welfare, Republic of Korea. (A010250)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5027.