A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer
Open accessAbstract
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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Patients with 'hot spot' PIK3CA mutations and undetectable or low PTEN measured by IHC exhibited a poorer outcome after treatment with chemotherapy and trastuzumab compared to patients without those alterations.
“Patients with ‘hot spot’ PIK3CA mutations and undetectable or low PTEN measured by IHC, exhibited a poorer outcome after treatment with chemotherapy and trastuzumab compared to patients without those alterations (Berns et al., 2007; Dave et al., 2011; Esteva et al., 2010).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Berns et al., 2007
Using a large-scale siRNA genetic screen, PTEN was identified as the only gene whose knockdown conferred trastuzumab resistance.
“Using a large-scale siRNA genetic screen, they identified PTEN as the only gene whose knockdown conferred trastuzumab resistance (Berns et al., 2007).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Berns et al., 2007
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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
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 12
- Issue
- 4
- Pages
- 395-402
- ISSN
- 1535-6108 (ISSN-L)
- 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
- 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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