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AZD6244 inhibits cisplatin-induced ERK1/2 activation and potentiates cisplatin-associated cytotoxicity in K-ras G12D preclinical models

Authors
 Eun Young Kim  ;  Arum Kim  ;  Se Kyu Kim  ;  Yoon Soo Chang 
Citation
 Cancer Letters, Vol.358(1) : 85-91, 2015 
Journal Title
 Cancer Letters 
ISSN
 0304-3835 
Issue Date
2015
MeSH
Animals ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Bcl-2-Like Protein 11 ; Benzimidazoles/administration & dosage* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Cisplatin/administration & dosage ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Humans ; MAP Kinase Kinase 1/biosynthesis ; MAP Kinase Kinase 1/genetics* ; MAP Kinase Signaling System/genetics* ; Membrane Proteins/metabolism ; Mice ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins p21(ras) ; ras Proteins/genetics*
Keywords
Bcl2-like 11 (BIM) ; Cisplatin ; KRAS ; MEK1/2 inhibitor ; NSCLC
Abstract
Although cisplatin has been widely used as a component of standard treatments for advanced non-small cell lung cancers (NSCLC) with KRAS-activating mutations, clinical outcomes remain suboptimal. Among the resistance mechanisms to cisplatin, activation of the MAPK cascade, which plays an important role in cancer cell stress and death, offers a promising therapeutic target. Using KRAS-mutant NSCLC cells and a mouse model, we evaluated the efficacy of adding the MEK1/2 inhibitor AZD6244 as an addition for cisplatin-based chemotherapy. Cisplatin increased phosphorylation of MEK1/2 and ERK1/2 and reduced Bcl-2 like 11 (BIM) expression in NSCLC cells and the mouse model. BIM silencing in NSCLC cells using shRNA led to a blunted cytotoxic response to cisplatin, while prevention of BIM loss with the MEK1/2 inhibitor synergized cisplatin-mediated cell death. The combination of cisplatin and AZD6244 yielded a superior response to cisplatin alone in K-ras mice. In conclusion, an MEK1/2 inhibitor potentiated the anti-tumor effects of cisplatin in KRAS-dependent lung cancer cells and an animal model through inhibition of BIM degradation. These findings warrant further studies of clinical applications of MEK1/2 inhibitors in cisplatin-based chemotherapy for lung cancer.
Full Text
http://www.sciencedirect.com/science/article/pii/S030438351400799X
DOI
10.1016/j.canlet.2014.12.041
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Se Kyu(김세규)
Kim, A Rum(김아름)
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139308
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