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Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway.
Cancer Res. 2002 Jun 01; 62(11):3132-7.CR

Abstract

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.

Authors+Show Affiliations

Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL 33612, USA. Munstepn@moffitt.usf.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12036925

Citation

Münster, Pamela N., et al. "Degradation of HER2 By Ansamycins Induces Growth Arrest and Apoptosis in Cells With HER2 Overexpression Via a HER3, Phosphatidylinositol 3'-kinase-AKT-dependent Pathway." Cancer Research, vol. 62, no. 11, 2002, pp. 3132-7.
Münster PN, Marchion DC, Basso AD, et al. Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. Cancer Res. 2002;62(11):3132-7.
Münster, P. N., Marchion, D. C., Basso, A. D., & Rosen, N. (2002). Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. Cancer Research, 62(11), 3132-7.
Münster PN, et al. Degradation of HER2 By Ansamycins Induces Growth Arrest and Apoptosis in Cells With HER2 Overexpression Via a HER3, Phosphatidylinositol 3'-kinase-AKT-dependent Pathway. Cancer Res. 2002 Jun 1;62(11):3132-7. PubMed PMID: 12036925.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. AU - Münster,Pamela N, AU - Marchion,Douglas C, AU - Basso,Andrea D, AU - Rosen,Neal, PY - 2002/5/31/pubmed PY - 2002/7/18/medline PY - 2002/5/31/entrez SP - 3132 EP - 7 JF - Cancer research JO - Cancer Res VL - 62 IS - 11 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/12036925/Degradation_of_HER2_by_ansamycins_induces_growth_arrest_and_apoptosis_in_cells_with_HER2_overexpression_via_a_HER3_phosphatidylinositol_3'_kinase_AKT_dependent_pathway_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12036925 DB - PRIME DP - Unbound Medicine ER -