Study on resistance of lung cancer cells to inhibitor of EGF receptor tyrosine kinase

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Despite the dramatic efficacy of gefitinib and erlotinib in non-small cell lung cancer (NSCLC) patients with EGFR mutations, all patients ultimately develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). A secondary mutation in EGFR (T790M) and MET amplification have been identified as major mechanisms of acquired resistance to EGFR-TKIs. However, it is still important to identify additional mechanisms of resistance and to overcome acquired resistance to EGFR-TKIs in NSCLC patients. We previously reported that EGFR-TKI AG1478 induces apoptosis in PC-9 cells, a gefitinib-sensitive human NSCLC cell line with a mutation (delE746-A750) in tyrosine kinase domain of their EGFR. In this study, we repeatedly treated PC-9 cells with a high concentration of AG1478 (500 nM) and isolated AG1478-resistant cell lines. Expression level of ErbB3 in these resistant cells was extremely low as compared with that of PC-9 cells. Furthermore, PC-9 cells became resistant to AG1478, when their Erb … More B3 expression was down-regulated by siRNA. Therefore, the apoptosis-inducing action of AG1478 was correlated with the expression level of ErbB3. These results indicate that ErbB3 served to couple EGFR to the cell survival pathway in PC-9 cells and that the resistant cells could find a way to effectively activate survival signaling independent of.We next treated PC-9 cells with a lower concentration of AG1478 (50 nM) and isolated another series of AG1478-resistant cell lines. In PC-9 cells, AG1478 decreased the expression of the MAPK phosphatase-1(MKP-1) and intensively stimulated phosphorylation of JNK. Further, AG1478 induced the accumulation of proapoptotic Bcl-2 family protein Bim in mitochondria. However, in the resistant cell lines, expression level of MKP-1 was still high after AG1478 treatment, and neither JNK phosphorylation nor accumulation of Bim was increased. These results indicate that translocation of Bim to mitochondria through the MKP-1/JNK pathway is critical for EGFR-TKI-induced apoptosis in PC-9 cells and that continuous high-level expression of MKP-1 leads to resistance to EGFR-TKIs. Less