Cited 13 times in

Sorafenib and Mek inhibition is synergistic in medullary thyroid carcinoma in vitro.

Authors
 Yoon Woo Koh ; Manisha H Shah ; Matthew D Ringel ; Motoyasu Saji ; David Jarjoura ; Kyle Porter ; Chaojie Wang ; Victoria J Brendel ; Bon Seok Koo ; Samantha K McCarty ; Kitty Agarwal 
Citation
 Endocrine-Related Cancer, Vol.19(1) : 29~38, 2012 
Journal Title
 Endocrine-Related Cancer 
ISSN
 1351-0088 
Issue Date
2012
Abstract
Clinical trials using kinase inhibitors have demonstrated transient partial responses and disease control in patients with progressive medullary thyroid cancer (MTC). The goal of this study was to identify potential combinatorial strategies to improve on these results using sorafenib, a multikinase inhibitor with activity in MTC, as a base compound to explore signaling that might predict synergystic interactions. Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to sorafenib, everolimus, and AZD6244 alone and in combination. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT) and poly (ADP-ribose) polymerase (PARP) cleavage assays were performed to measure cell survival and apoptosis. Western blots were performed to confirm activity of the compounds and to determine possible mechanisms of resistance and predictors of synergy. As a solitary agent, sorafenib was the most active compound on MTT assay. Western blots confirmed that sorafenib, everolimus, and AZD6244 inhibited their anticipated targets. At concentrations below its IC(50), sorafenib-treated TT and MZ-CRC-1 cells demonstrated transient inhibition and then re-activation of Erk over 6 h. In concordance, synergistic effects were only identified using sorafenib in combination with the Mek inhibitor AZD6244 (P<0.001 for each cell line). Cells treated with everolimus demonstrated activation of Akt and Ret via TORC2 complex-dependent and TORC2 complex-independent mechanisms respectively. Everolimus was neither additive nor syngergistic in combination with sorafenib or AZD6244. In conclusion, sorafenib combined with a Mek inhibitor demonstrated synergy in MTC cells in vitro. Mechanisms of resistance to everolimus in MTC cells likely involved TORC2-dependent and TORC2-independent pathways.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/90165
DOI
10.1530/ERC-11-0155
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Otorhinolaryngology
Yonsei Authors
사서에게 알리기
  feedback
Files in This Item:
T201201745.pdfDownload
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse