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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Vydané v:	Cancer cell Ročník 12; číslo 4; s. 395
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.10.2007
Predmet:	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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Popis
Shrnutí:	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.
Bibliografia:	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