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
Hauptverfasser: Berns, Katrien, Horlings, Hugo M, Hennessy, Bryan T, Madiredjo, Mandy, Hijmans, E Marielle, Beelen, Karin, Linn, Sabine C, Gonzalez-Angulo, Ana Maria, Stemke-Hale, Katherine, Hauptmann, Michael, Beijersbergen, Roderick L, Mills, Gordon B, van de Vijver, Marc J, Bernards, René
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.10.2007
Schlagworte:
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
ISSN:1535-6108
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Beschreibung
Zusammenfassung: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.
Bibliographie:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
ISSN:1535-6108
DOI:10.1016/j.ccr.2007.08.030