p53 Enhances Gefitinib-Induced Growth Inhibition and Apoptosis by Regulation of Fas in Non–Small Cell Lung Cancer

Abstract

Treatment with gefitinib, a specific inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), has resulted in dramatic responses in some patients with nonsmall cell lung cancer (NSCLC). Most patients who respond to gefitinib have EGFR-TK mutations; however, >10% of patients with EGFR-TK mutations do not respond. Similarly, some patients without EGFR-TK mutations respond to this drug, suggesting that other factors determine sensitivity to gefitinib. Aberrations of the tumor suppressor gene p53 are frequently associated with drug resistance. In this study, we investigated the role of p53 in growth-inhibitory and apoptotic effects of gefitinib in the human NSCLC cell lines NCI-H1299 and A549, which have no EGFR-TK mutations. NCI-H1299 cells, which had a p53-null genotype, were more resistant to gefitinib compared with A549 cells, which were wild-type p53 (IC 50 , 40 Mmol/L in NCI-H1299 and 5 Mmol/L in A549). Treatment of A549 with gefitinib resulted in the translocation of p53 from cytosol to nucleus and the up-regulation of Fas, which was localized to the plasma membrane. In the stable H1299 cell line with tetracycline-inducible p53 expression, induced p53 enhanced growth inhibition and apoptosis by gefitinib through the up-regulation of Fas and restoration of caspase activation. A caspase inhibitor, Z-VAD-fmk, reduced these effects. Conversely, inhibition of p53 using antisense oligonucleotide in A549 caused a significant decrease in apoptosis by gefitinib and down-regulation of Fas under the same conditions. In conclusion, p53 may play a role in determining gefitinib sensitivity by regulating Fas expression in NSCLC.

HER2 overexpression reverses the relative resistance of EGFR-mutant H1975 cell line to gefitinib

“…Restoration of p53 to p53-defective H1299 cells can enhance the sensitivity to gefitinib (35). In the present study, the resistant of H1299 cells to gefitinib could not be reversed by the ectopic overexpression of HER2.…”

P53 and PTEN expression contribute to the inhibition of EGFR downstream signaling pathway by cetuximab

“…9 Recent data showed that sensitivity to gefitinib is affected by P53 mutation and that P53 inhibition induces a significant decrease in apoptosis induction by gefitinib. 10 Previous study already demonstrated that cetuximab inhibited the growth of wild-type p53 but not of mutated p53 cancer cells and hypothesized that resistance to cetuximab could relate to p53 mutation. 11 In addition, recent study showed that induction of P53 resulted in decreased in phosphorylated AKT activity in cell line, which did not express PTEN protein, thus highlighting that p53 was involved in regulation of survival PI3K/AKT pathway in epithelial tumors, and independently of PTEN expression.…”

Biomarkers for predicting response to tyrosine kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

“…Aberrations of p53 are usually associated with drug resistance. Recent data showed that human urothelial cells with loss of p53 function displayed reduced sensitivity to TKIs (27) and p53 is required for maximal sensitivity to gefitinib-induced apoptosis in non-small cell lung cancer (28). One point mutation (codon 135, cysteine to serine) was identified in the UM-UC-14 cells (data not shown).…”