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 p110alpha 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.