Integrin Beta1 Over-Expression Associates With Resistance to Tyrosine Kinase Inhibitor Gefitinib in Non-Small Cell Lung Cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib and erlotinib have been widely used in treating patients with advanced non-small cell lung cancer (NSCLC). However, acquired resistance to EGFR TKI almost occurs in every patient eventually. To identify its potential mechanism, we established a human NSCLC cell line PC9/AB2 which was 576-fold decrease in gefitinib sensitivity compared with its parental PC9 cell lines. No EGFR-T790M mutation or abnormal expression of c-Met protein was found in PC9/AB2 cells. Over-expression of integrin beta 1 was found, accompanied with increase of the cells' adhesion and migration. To further confirm the role of integrin beta 1 in gefitinib acquired resistance, we transferred its siRNA-expressing plasmid and its whole cDNA expressing plasmid into PC9/AB2 and into PC9 cells, respectively. The sensitivity of NSCLC cells to gefitinib was negatively correlated with integrin beta 1 expression levels. All these data suggest that up-regulation of integrin beta 1 might be an important factor for gefitinib resistance in NSCLC cell line PC9/AB2. J. Cell. Biochem. 111: 1565-1574, 2010. (C) 2010 Wiley-Liss, Inc.