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Enhancement of Chemosensitivity by Tyrphostin AG825 in High-p185^neu Expressing Non-Small Cell Lung Cancer Cells¹

Department of Medicine, School of Medicine, National Yang-Ming University [C-M. T., R-P. P.], Taipei, Taiwan 11217, Republic of China; Section of Thoracic Oncology [C-M. T., K-T. C., C-C. C.], Chest Department [R-P. P], and Section of General Surgery, Department of Surgery [L-H. W], Veterans General Hospital-Taipei, Taipei, Taiwan 11217, Republic of China; and Departments of Biological Chemistry [A. L., A. G.] and Organic Chemistry [A. G.], Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel

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 doxorubicin, 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.

¹ This work is supported in part by National Science Council Grant NSC-84-2331-B-075-002, by grants from Veterans General Hospital-National Yang-Ming University Joint Research Program, Tsou's Foundation (VGHYM-S8507), and the Lung Cancer Foundation in memory of Dr. K. S. Lu. The work of A. L. and A. G. was partially supported by SUGEN, Inc., Redwood City, CA.

² To whom requests for reprints should be addressed.

Received 8/30/95. Accepted 1/ 3/96.

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