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[Cancer Research 61, 4892-4900, June 15, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

Down-Regulation of the erbB-2 Receptor by Trastuzumab (Herceptin) Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Breast and Ovarian Cancer Cell Lines that Overexpress erbB-2

Mauricio Cuello, Seth A. Ettenberg, Amy S. Clark, Maccon M. Keane1, Reuben H. Posner, Marion M. Nau, Phillip A. Dennis and Stan Lipkowitz2

Genetics Department [M. C., S. A. E., M. M. K., R. H. P., M. M. N., S. L.] and Developmental Therapeutics Department [A. S. C., P. A. D.], Medicine Branch, National Cancer Institute, Bethesda, Maryland 20889; Molecular and Cell Biology Program, Uniform Services University of the Health Sciences, Bethesda, Maryland 20889 [S. A. E., S. L.]; and Department of Obstetrics and Gynecology, Faculty of Medicine, Pontific Catholic University of Chile, Santiago, Chile [M. C.]

We investigated whether combined treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and trastuzumab could enhance the specific killing of cells that overexpress the erbB-2 receptor. The combination resulted in an enhancement of TRAIL-mediated apoptosis in all cell lines overexpressing erbB-2 receptor compared with either reagent alone. In contrast, there was no effect in cell lines with low levels of the erb-B2 receptor. Trastuzumab treatment resulted in down-regulation of the erbB-2 receptor in all erbB-2-overexpressing cell lines. Similar enhancement of TRAIL toxicity was observed when the erbB-2 receptor was down-regulated using antisense oligodeoxynucleotides. Down-regulation of the erbB-2 receptor protein by trastuzumab or antisense oligodeoxynucleotides decreased Akt kinase activation but not mitogen-activated protein kinase activation. Down-regulation of Akt kinase activity by a phosphatidylinositol 3'-kinase inhibitor (LY294002) also resulted in enhancement of TRAIL-mediated apoptosis. Expression of a constitutively active form of Akt kinase in an erbB-2-overexpressing cell line completely abrogated the increase in TRAIL-mediated apoptosis by trastuzumab and significantly reduced the biological effect of either reagent alone. Therefore, down-regulation of the erbB-2 receptor by trastuzumab enhances TRAIL-mediated apoptosis by inhibiting Akt kinase activity. These data suggest that the combination of trastuzumab and TRAIL may allow enhanced therapeutic efficacy and specificity in the treatment of erbB-2-overexpressing tumors.




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