Abstract 347: Mechanism of c-Met TKI resistance and role of epithelial mesenchymal transition in melanoma

Autor: Ichwaku Rastogi, Sunil Palani, Neelu Puri, Supriya Rajanna
Rok vydání: 2015
Předmět:
Zdroj: Cancer Research. 75:347-347
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2015-347
Popis: Various tyrosine kinase inhibitors (TKI’s) are approved for the treatment of melanoma, but their efficacies are limited due to development of drug resistance. To analyze the resistance to c-Met inhibitors we used two melanoma cell lines: MU which has mutated BRAF (V600E +ve) and RU which has wild type BRAF. These cell lines were also made resistant to c-Met inhibitor, SU11274 by growing them in progressively increasing concentrations of drug. In earlier studies we observed activation of Wnt pathway in both of the aforementioned cell lines indicating the role of active β-Catenin in transcription and hence cell proliferation. β-Catenin levels when localized and accumulated in the nucleus binds to TCF/LEF and activates transcription. The level of β-Catenin in the cytosol is regulated by the adherens junction proteins (E-Cadherin) along with the Wnt pathway. Increased levels of β-Catenin might be a possible result of loss of E-Cadherin which is related to epithelial mesenchymal transition. During epithelial mesenchymal transition (EMT) cells transition from epithelial (attached, non-migratory) to mesenchymal (unattached and migratory) cells which promotes metastasis. We examined the role of EMT in the development of resistance in the c-Met TKI resistant melanoma cell lines. We quantified the β-Catenin activity using luciferase assay and observed a 5 fold upregulation in the SU11274 resistant MU cells when compared to MU parental cells in the presence of HGF. Additionally, we performed immunoblotting, where we observed modulation in EMT related proteins in MU and RU parental and resistant cells. E-Cadherin, ZO-1, Claudin-1 and Slug were found to be downregulated 1.5 - 2.7 fold, 1.5 - 2.0 fold, 2 - 9 fold and 1.5 - 2 fold respectively and N-Cadherin and β-Catenin were found to be upregulated 1.8 - 5.3 and 2.4 - 3.7 fold respectively in the SU11274 resistant MU cells in the presence and absence of HGF and SU11274 treatments. Similarily we observed upregulation of β-Catenin by 1.7 fold and downregulation of E-Cadherin and ZO-1 by 2 - 3.5 fold and 6 - 9 fold respectively in SU11274 resistant RU cells when compared to RU parental cells in the presence and absence of HGF and SU11274 treatments. Further studies are being carried to understand the role of EMT in the development of this acquired resistance. These results may help in development of novel therapies for melanoma patients or may help in increasing the efficacy and beneficence from the currently available therapeutics. Citation Format: Supriya Rajanna, Ichwaku Rastogi, Sunil Palani, Neelu Puri. Mechanism of c-Met TKI resistance and role of epithelial mesenchymal transition in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 347. doi:10.1158/1538-7445.AM2015-347
Databáze: OpenAIRE
Externí odkaz: