A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer
A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastu...
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| Veröffentlicht in: | Cancer cell Jg. 12; H. 4; S. 395 |
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| Hauptverfasser: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
United States
01.10.2007
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| ISSN: | 1535-6108 |
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| Abstract | A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy. |
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| AbstractList | A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy. A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy. |
| Author | Stemke-Hale, Katherine van de Vijver, Marc J Berns, Katrien Madiredjo, Mandy Beelen, Karin Hauptmann, Michael Bernards, René Linn, Sabine C Horlings, Hugo M Hijmans, E Marielle Gonzalez-Angulo, Ana Maria Hennessy, Bryan T Mills, Gordon B Beijersbergen, Roderick L |
| Author_xml | – sequence: 1 givenname: Katrien surname: Berns fullname: Berns, Katrien organization: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands – sequence: 2 givenname: Hugo M surname: Horlings fullname: Horlings, Hugo M – sequence: 3 givenname: Bryan T surname: Hennessy fullname: Hennessy, Bryan T – sequence: 4 givenname: Mandy surname: Madiredjo fullname: Madiredjo, Mandy – sequence: 5 givenname: E Marielle surname: Hijmans fullname: Hijmans, E Marielle – sequence: 6 givenname: Karin surname: Beelen fullname: Beelen, Karin – sequence: 7 givenname: Sabine C surname: Linn fullname: Linn, Sabine C – sequence: 8 givenname: Ana Maria surname: Gonzalez-Angulo fullname: Gonzalez-Angulo, Ana Maria – sequence: 9 givenname: Katherine surname: Stemke-Hale fullname: Stemke-Hale, Katherine – sequence: 10 givenname: Michael surname: Hauptmann fullname: Hauptmann, Michael – sequence: 11 givenname: Roderick L surname: Beijersbergen fullname: Beijersbergen, Roderick L – sequence: 12 givenname: Gordon B surname: Mills fullname: Mills, Gordon B – sequence: 13 givenname: Marc J surname: van de Vijver fullname: van de Vijver, Marc J – sequence: 14 givenname: René surname: Bernards fullname: Bernards, René |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17936563$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Adult Aged Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Breast Neoplasms - drug therapy Breast Neoplasms - enzymology Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - mortality Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases Cohort Studies Disease Progression Drug Resistance, Neoplasm - genetics Female Gene Expression Profiling - methods Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Middle Aged Mutation Oligonucleotide Array Sequence Analysis Patient Selection Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - metabolism RNA Interference RNA, Small Interfering - metabolism Signal Transduction - drug effects Signal Transduction - genetics Transduction, Genetic Trastuzumab Treatment Outcome |
| Title | A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer |
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| Volume | 12 |
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