Enhancement of chemosensitivity by tyrphostin AG825 in high-p185^neu expressing non-small cell lung cancer cells

The HER-2/neu gene product, p185^neu, is a membrane-bound receptor with tyrosine kinase activity. High levels of p185^neu is correlated with intrinsic chemoresistance of non-small cell lung cancer (NSCLC) cell lines. We investigated the effects of tyrphostin AG825, a selective tyrosine kinase inhibitor preferentially inhibiting HER-2/neu kinase, on the chemosensitivities and on the drug-induced cell cycle changes of NSCLC cell lines that expressed different levels of p185^neu. Compared to the low-p185^neu expressing cell lines, we found that the high-p185^neu expressing cell lines were more resistant to doxorubidn, etoposide, and cis-diamminedichloroplatinum(II) but more sensitive to AG825. AG825 was able to significantly enhance the chemosensitivities of the high-p185^neu expressing cell lines, whereas it had little effect on the chemosensitivities of the low-p185^neu expressing cells, with a few exceptions in which minor antagonistic effects were observed. Although high concentrations of AG825 could reduce the drug-induced G₂ arrest that was accompanied by the activation of phosphorylated p34^cdc2, we failed to find any remarkably differential effects of AG825 on drug-induced G₂ arrest and the accompanying phosphorylation status of p34^cdc2 of the high- and the low-p185^neu expressing cell lines. In summary, tyrphostin AG825 can enhance chemosensitivity in high- but not in low-p185^neu expressing NSCLC cell lines. This differential effect cannot be explained by the alterations of drug-induced cell cycle changes by AG825. Our results provide a rationale to develop p185^neu-specific tyrphostin and to test them in combination with anticancer agents in vivo and in clinical trials.