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 β1 was found, accompanied with increase of the cells' adhesion and migration. To further confirm the role of integrin β1 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 β1 expression levels. All these data suggest that up-regulation of integrin β1 might be an important factor for gefitinib resistance in NSCLC cell line PC9/AB2.

Ju L ，Zhou C ，Li W ，Yan L ... -  《-》

[Drug resistance mechanism of non small cell lung cancer PC9/AB2 cell line with acquired drug resistance to gefitinib].

Ju LX ，Zhou CC ，Tang L ，Zhao YM ，Yang XJ ，Su B ，Meng SY ，Li W ，Yan LH ，Ding YM ... -  《-》

Antitumor activity of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in non-small cell lung cancer cell lines correlates with gene copy number and EGFR mutations but not EGFR protein levels.

Helfrich BA ，Raben D ，Varella-Garcia M ，Gustafson D ，Chan DC ，Bemis L ，Coldren C ，Barón A ，Zeng C ，Franklin WA ，Hirsch FR ，Gazdar A ，Minna J ，Bunn PA Jr ... -  《CLINICAL CANCER RESEARCH》

The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors.

Rho JK ，Choi YJ ，Lee JK ，Ryoo BY ，Na II ，Yang SH ，Lee SS ，Kim CH ，Yoo YD ，Lee JC ... -  《-》

Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC.

Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.

Terai H ，Soejima K ，Yasuda H ，Nakayama S ，Hamamoto J ，Arai D ，Ishioka K ，Ohgino K ，Ikemura S ，Sato T ，Yoda S ，Satomi R ，Naoki K ，Betsuyaku T ... -  《-》