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[Cancer Research 62, 3132-3137, June 1, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

Degradation of HER2 by Ansamycins Induces Growth Arrest and Apoptosis in Cells with HER2 Overexpression via a HER3, Phosphatidylinositol 3'-Kinase-AKT-dependent Pathway1

Pamela N. Münster2, Douglas C. Marchion, Andrea D. Basso and Neal Rosen

Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 [P. N. M., D. C. M.], and Department of Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [A. D. B., N. R.]

Breast cancers with high expression of HER2 are associated frequently with aggressive, poor prognosis disease and resistance to chemotherapy-induced apoptosis. Geldanamycin and its less toxic analogue, 17- (allylamino)-17-demethoxygeldanamycin (17-AAG) are ansamycin antibiotics that bind to a highly conserved pocket in the hsp 90 chaperone protein and inhibit its function. Hsp 90 is required for the refolding of proteins during environmental stress and the conformational maturation of certain signaling proteins. Among the most sensitive targets of 17-AAG are the HER kinases. Therefore, tumors that are dependent on these kinases may be especially sensitive to 17-AAG either alone or in combination with chemotherapy. In this study we demonstrate that cells that overexpress HER2 are 10–100-fold more sensitive to 17-AAG than cancer cells expressing low levels of HER2. We found that HER2 is degraded in several cell lines, but only cell lines with high levels of HER2 are sensitive to the drug. The effects of 17-AAG on growth and apoptosis are because of inhibition of signaling through HER2-HER3, phosphatidylinositol 3'- kinase. The absence of HER3 and the introduction of constitutively active p110{alpha} rendered cells with high HER2 expression more resistant to 17-AAG.

These findings suggest that 17-AAG may be useful for the treatment of breast cancer cells with high levels of HER2. However, the overexpression of HER2 alone may not be predictive of response, because the coexpression of HER3 and the activation of phosphatidylinositol 3'-kinase may play a crucial role in the response of these cells to 17-AAG and other drugs directed against HER2. These observations have important clinical implications because they may help to identify patients that are most likely to benefit from 17-AAG and may explain resistance to Herceptin as seen in many patients.




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