Abstract 1908: MDR1 gene overexpression confers resistance to C-MET inhibitor in multidrug resistant cancer cell line

Abstract

c-MET signaling is implicated in a wide variety of human malignancies. Hepatocyte growth factor (HGF) binding to the proto-oncogenic c-MET receptor lead to activate multiple tyrosine kinase signaling pathway. Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Recently, several reports have indicated that inhibition of c-MET signaling induced apoptosis in a variety of cancer cells and recognized as a novel anticancer therapy approach. Previous study from our laboratory also showed that the higher mRNA expression level of HGF, and its downstream genes including HGF receptor (c-Met) and urokinase (uPA) were detected in drug resistant Dx5-C5 cell compared with parental human uterus sarcoma MES-SA cell line. Furthermore, report indicated that the constitutive expression of P-glycoprotein (P-gp) is involved in the HGF/MET related pathway of MDR-positive human hepatocellular carcinoma cell line. Moreover, MDR1 gene overexpressed leukemia cell line also shown more resistance to tyrosine kinase inhibitor imatinib mesylate. These finding suggested that chemoresistant cancer cells may also develop a similar mechanism to against c-MET inhibitor. Our results shown: when treated both cell cancer lines with c-MET inhibitor PHA665752, we found that compared to parental MES-SA cells, the Dx5-C5 cells with highly expressed P-gp was more resistant to PHA665752, the resistance was also reversed by co-treatment of MDR inhibitor verapamil and PHA665752. In addition, when transfection of c-MET shRNA into Dx5-C5 and MES-SA cell line for 48 hrs, we found that the viability was decreased in the c-MET shRNA transfected Dx5-C5 cell line in a dose dependent manner but not in the MES-SA cell line. In conclusion, our study demonstrated that existence of P-glycoprotein in MDR cell line would attenuate c-MET inhibitor induced cell death and may help us to develop a new strategy for treatment of multiple drug resistance cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1908. doi:1538-7445.AM2012-1908