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p185^c-erbB-2 Signaling Enhances Cisplatin-induced Cytotoxicity in Human Breast Carcinoma Cells: Association between an Oncogenic Receptor Tyrosine Kinase and Drug-induced DNA Repair¹

Departments of Medicine [C. L. A., A. R. W., S. D. H., S. J. S], Cell Biology [C. L. A.], and Microbiology and Immunology [S. J. S.], Vanderbilt University School of Medicine, and the Department of Veteran Affairs Medical Center [C. L. A., S. J. S.], Nashville, Tennessee 37232; Berlex Biosciences, Alameda, California 94501 [L. K. S.]; and Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [M. C. P., D. M. L-L.]

The c-erbB-2 (HER-2/neu) protooncogene encodes an M_r 185,000 transmembrane glycoprotein with intrinsic tyrosine kinase activity. Agonistic antibodies against p185^c-erbB-2 enhance the cytotoxic effect of the DNA alkylator, cisplatin, against c-erbB-2-overexpressing human carcinoma cells (Hancock et al., Cancer Res., 51: 4575–4580, 1991). We have studied the possible association between receptor signal transduction and cisplatin-mediated cytotoxicity utilizing the SKBR-3 human breast cancer cell line and the anti-p185 TAb 250 IgG1. TAb 250 induced tyrosine phosphorylation of p185 and the receptor substrate phospholipase C-1, as well as rapid association of these molecules in vivo. Simultaneously with phosphorylation, phospholipase C-1 catalytic activity measured in a [³H]phosphatidylinositol-4,5-bisphosphate hydrolysis assay was increased 61 ± 12% above control. Preincubation of SKBR-3 cells with the tyrosine kinase inhibitor tyrphostin 50864-2 abrogated the enhancement of drug-mediated cell kill induced by TAb 250. The supraadditive drug/antibody effect was not seen in SKBR-3 cells with TAb 263, an anti-p185 IgG1 that does not induce receptor signaling or with TAb 250 in MDA-468 breast cancer cells which do not overexpress c-erbB-2. In addition, transforming growth factor- increased cisplatin-induced cytotoxicity against NIH 3T3 cells overexpressing an epidermal growth factor receptor/c-erbB-2 chimera. Cellular uptake or efflux of [^195mPt]cisplatin by SKBR-3 cells was not altered by TAb 250. Finally, simultaneous treatment of SKBR-3 cells with TAb 250 and cisplatin increased cisplatin/DNA intrastrand adduct formation and delayed the rate of adduct decay. Taken together these data support a direct association between p185^c-erbB-2 signal transduction and inhibition of cisplatin-induced DNA repair.

¹ Supported in part by Department of Veteran Affairs Merit Review grants (C. L. A. and S. J. S.), a grant from Berlex Biosciences (C. L. A.), and American Cancer Society Grant CB-2 (C. L. A.)

² C. L. A. is recipient of a Research Associate Career Development Award from the Department of Veteran Affairs. To whom requests for reprints should be addressed, at Department of Medicine/Oncology, Vanderbilt University, 22nd Avenue South, 1956 TVC, Nashville, TN 37232-5536.

³ Present address: Sugen Inc., 515 Galveston Drive, Redwood City, CA 94063.

Received 1/13/94. Accepted 5/11/94.

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