Document Detail

A novel treatment strategy for EGFR mutant NSCLC with T790M-mediated acquired resistance.
MedLine Citation:
PMID:  21953013     Owner:  NLM     Status:  Publisher    
The purpose was to identify novel kinase inhibitors for the treatment of genetic subsets of non-small cell lung cancer (NSCLC). NSCLC cell lines (n=8) with known oncogenic backgrounds (K-Ras, EGFR, and EML4-ALK) were exposed to several kinase inhibitors and analyzed for cell growth/cytotoxicity and signaling. Gö6976, a classical protein kinase C inhibitor, showed high potency against mutated EGFR and was further validated in vitro using additional NSCLC lines (n=4) and Ba/F3 models, and in vivo using a xenograft model. Gö6976 was identified to be a potent inhibitor of mutated EGFR with IC50 values from 0.033nM to 3.3µM and down regulating phosphorylation of EGFR, AKT, and ERK1/2 at concentrations in the range of the IC50 values. Gö6976 has only a minor effect on wild-type EGFR and cell lines independent of signaling from the mutant EGFR. Most importantly, the activity of Gö6976 remains unchanged despite the presence of the T790M-mediated resistance and it prevents the occurrence of this resistance in vitro. Gö6976 was also shown to significantly reduce tumor growth in an in vivo xenograft model with a EGFR mutated NSCLC cell line containing T790M. These findings demonstrate that Gö6976 acts as a potent inhibitor of mutant EGFR despite the presence of T790M, the most important mechanism of acquired resistance for EGFR tyrosine kinase inhibitors, in both in vitro and in vivo models. © 2011 Wiley-Liss, Inc.
Erika Taube; Elina Jokinen; Peppi Koivunen; Jussi P Koivunen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-9-27
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  -     ISSN:  1097-0215     ISO Abbreviation:  -     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-9-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 UICC.
Department of Medical Oncology and Radiotherapy, Oulu University, Hospital for Cell-Matrix Research, University of Oulu, Oulu, Finland.
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