PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer
There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial stud...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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NATURE PUBLISHING GROUP
2011
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| Online Access: | http://hdl.handle.net/20.500.11937/81904 |
| _version_ | 1848764442855079936 |
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| author | Serra, V. Scaltriti, M. Prudkin, L. Eichhorn, Pieter Ibrahim, Y.H. Chandarlapaty, S. Markman, B. Rodriguez, O. Guzman, M. Rodriguez, S. Gili, M. Russillo, M. Parra, J.L. Singh, S. Arribas, J. Rosen, N. Baselga, J. |
| author_facet | Serra, V. Scaltriti, M. Prudkin, L. Eichhorn, Pieter Ibrahim, Y.H. Chandarlapaty, S. Markman, B. Rodriguez, O. Guzman, M. Rodriguez, S. Gili, M. Russillo, M. Parra, J.L. Singh, S. Arribas, J. Rosen, N. Baselga, J. |
| author_sort | Serra, V. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation. © 2011 Macmillan Publishers Limited All rights reserved. |
| first_indexed | 2025-11-14T11:19:26Z |
| format | Journal Article |
| id | curtin-20.500.11937-81904 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:19:26Z |
| publishDate | 2011 |
| publisher | NATURE PUBLISHING GROUP |
| recordtype | eprints |
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| spelling | curtin-20.500.11937-819042021-01-08T05:08:45Z PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer Serra, V. Scaltriti, M. Prudkin, L. Eichhorn, Pieter Ibrahim, Y.H. Chandarlapaty, S. Markman, B. Rodriguez, O. Guzman, M. Rodriguez, S. Gili, M. Russillo, M. Parra, J.L. Singh, S. Arribas, J. Rosen, N. Baselga, J. Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Oncology Cell Biology Genetics & Heredity PI3K/mTOR HER2 feedback ERK BEZ235 PHASE-II TRASTUZUMAB RESISTANCE PATHWAY ACTIVATION ANTITUMOR-ACTIVITY PTEN RECEPTOR PIK3CA MUTATIONS GENE MEK There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation. © 2011 Macmillan Publishers Limited All rights reserved. 2011 Journal Article http://hdl.handle.net/20.500.11937/81904 10.1038/onc.2010.626 English http://creativecommons.org/licenses/by-nc-nd/3.0/ NATURE PUBLISHING GROUP fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Oncology Cell Biology Genetics & Heredity PI3K/mTOR HER2 feedback ERK BEZ235 PHASE-II TRASTUZUMAB RESISTANCE PATHWAY ACTIVATION ANTITUMOR-ACTIVITY PTEN RECEPTOR PIK3CA MUTATIONS GENE MEK Serra, V. Scaltriti, M. Prudkin, L. Eichhorn, Pieter Ibrahim, Y.H. Chandarlapaty, S. Markman, B. Rodriguez, O. Guzman, M. Rodriguez, S. Gili, M. Russillo, M. Parra, J.L. Singh, S. Arribas, J. Rosen, N. Baselga, J. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer |
| title | PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer |
| title_full | PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer |
| title_fullStr | PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer |
| title_full_unstemmed | PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer |
| title_short | PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer |
| title_sort | pi3k inhibition results in enhanced her signaling and acquired erk dependency in her2-overexpressing breast cancer |
| topic | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Oncology Cell Biology Genetics & Heredity PI3K/mTOR HER2 feedback ERK BEZ235 PHASE-II TRASTUZUMAB RESISTANCE PATHWAY ACTIVATION ANTITUMOR-ACTIVITY PTEN RECEPTOR PIK3CA MUTATIONS GENE MEK |
| url | http://hdl.handle.net/20.500.11937/81904 |