[1856] Wnt Signal Pathway and EMT Gene Expressions Are Possible Mechanisms of Acquired Resistance of EGFR-TKI

X Xu, JC Lee, J-H Chung. Seoul National University College of Medicine, Seoul, Korea; Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea; Korea Cancer Certer Hospital, Korea Institute of Radiological &Medical Science, Seoul, Korea

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib have been used for the treatment of non-small cell lung cancer, but drug resistance eventually develops in most patients despite the initial good response. The acquired resistance of EGFR-TKI was found in the HCC827 lung cancer cell line, which harbored L858R point mutation without T790M mutation or MET gene amplification. The molecular mechanism of EGFR-TKI resistance is still questionable.
Design: To address the possible genetic mechanisms on EGFR-TKI resistance, we compared gene expression profiles with the use of DNA microarrays between HCC827 cell line and HCC 827 sublines showing EGFR-TKI resistance (HCC827/CLR). We assessed the level of Wnt signaling activity and EMT markers by western blotting in the cell lines.
Results: Two significant gene expressions- Wnt signal pathway and Epithelial Mesenchymal Transition (EMT)-were identified. Wnt 1, 3, 5A, 6, 9A, GSK 3β, Axin2, LRP 6, 10, 12 and FZD2, 4, 7 genes were increased in HCC827/CLR sublines compared to HCC827 cell lines. Adhesion molecule genes including Integrin, E-cadherin, N-cadherein, B-catenin were decreased. On the contrary, EMT markers, such as Snail, Slug, SIP-1, Twist, Vimentin were increased in HCC827 CLR. HCC827/CLR showed morphologic features of Epithelial-to-mesenchymal transition (EMT), such as loss of polarity and spindle shaped morphology.
Conclusions: Wnt signal pathway gene and EMT related gene expressions are possible genetic mechanisms of acquired resistance of EGFR-TKI.
Category: Pulmonary

Monday, March 22, 2010 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 244, Monday Morning

 

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