Cited by 1,627PI3K/AKT/mTOR signaling in cancerHER2/EGFR in Cancer ResearchBreast Cancer Treatment Studies

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A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer

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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·2007·Cancer Cell

DOI 10.1016/j.ccr.2007.08.030

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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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Authors: Berns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., Linn, S. C., Gonzalez-Angulo, A. M., Stemke-Hale, K., Hauptmann, M., Beijersbergen, R. L., Mills, G. B., van de Vijver, M. J., & Bernards, R.
Affiliations: The Netherlands Cancer Institute (NL)
The University of Texas MD Anderson Cancer Center (US)
Corresponding author: Bernards, René
ORCID: Berns, Katrien
Horlings, Hugo M.
Hennessy, Bryan T.
Hijmans, E. Marielle
Beelen, Karin
Linn, Sabine C.
Gonzalez-Angulo, Ana Maria
Hauptmann, Michael
Beijersbergen, Roderick L.
Mills, Gordon B.
Bernards, René
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2007-10
Volume: 12
Issue: 4
Pages: 395-402
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2007.08.030
OpenAlex: W2020372547
Cited by: 1,627
References: 22
Citations by year: 2026: 26 · 2025: 44 · 2024: 33 · 2023: 81 · 2022: 69 · 2021: 54 · 2020: 63 · 2019: 70 · 2018: 88 · 2017: 74 · 2016: 102 · 2015: 116 · 2014: 118 · 2013: 144 · 2012: 123
FWCI: 37.98
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2116 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
Funders: National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords: trastuzumab resistance, breast cancer, PI3K signaling, PTEN, PIK3CA mutation, RNAi screen, drug sensitivity, prognostic factors, HER2-positive breast cancer, treatment response prediction
MeSH terms: Trastuzumab, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Middle Aged, Mutation, Transduction, Genetic, Biomarkers, Tumor, Cohort Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Treatment Outcome, Disease Progression, Patient Selection, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, PTEN Phosphohydrolase, Kaplan-Meier Estimate, Class I Phosphatidylinositol 3-Kinases, Antibodies, Monoclonal, Humanized

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A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer

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