Enhancement of chemosensitivity and programmed cell death by tyrosine kinase inhibitors correlates with EGFR expression in non-small cell lung cancer cells.

Epidermal growth factor receptor (EGFR) is a 170 kD transmembrane glycoprotein with tyrosine kinase activity. Overexpression of the EGFR has been detected in many human cancers, including non-small cell lung cancer (NSCLC), and is correlated with poor prognosis and chemoresistance. We investigated the effects of tyrosine kinase inhibitors on chemosensitivity and chemotherapeutic drug-induced programmed cell death in NSCLC cell lines that express different levels of EGFR. NCI-H596 cells, which strongly express EGFR, were more resistant to the growth inhibitory effects of cisplatin, doxorubicin and etoposide than were NCI-H358 cells, which only weakly express EGFR. Both genistein, a general tyrosine kinase inhibitor, and tyrphostin AG 1478, a tyrosine kinase inhibitor specific for EGFR, inhibited phosphorylation of EGFR in NCI-H596. Combinations of genistein or tyrphostin AG 1478 with cisplatin, doxorubicin, or etoposide enhanced the antiproliferative effects and induced programmed cell death in NCI-H596 cells, whereas no such additive effects were observed in NCI-H358 cells. The programmed cell death induced by these agents involved CPP32 mediated PARP cleavage and DNA fragmentation. These results indicate that tyrosine kinase inhibitors in combination with chemotherapeutic drugs may prove to be a viable therapeutic strategy for the treatment of those types of NSCLC that demonstrate strong expression of EGFR.