A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer

Katrien Berns; Hugo M Horlings; Bryan T Hennessy; Mandy Madiredjo; E Marielle Hijmans; Karin Beelen; Sabine C Linn; Ana Maria Gonzalez-Angulo; Katherine Stemke-Hale; Michael Hauptmann; Roderick L Beijersbergen; Gordon B Mills; Marc J van de Vijver; René Bernards

doi:10.1016/j.ccr.2007.08.030

A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer

Cancer Cell. 2007 Oct;12(4):395-402. doi: 10.1016/j.ccr.2007.08.030.

Authors

Katrien Berns¹, Hugo M Horlings, Bryan T Hennessy, Mandy Madiredjo, E Marielle Hijmans, Karin Beelen, Sabine C Linn, Ana Maria Gonzalez-Angulo, Katherine Stemke-Hale, Michael Hauptmann, Roderick L Beijersbergen, Gordon B Mills, Marc J van de Vijver, René Bernards

Affiliation

¹ Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

PMID: 17936563
DOI: 10.1016/j.ccr.2007.08.030

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.

Publication types

Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Patient Selection
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism*
RNA Interference
RNA, Small Interfering / metabolism
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / metabolism
Signal Transduction / drug effects*
Signal Transduction / genetics
Transduction, Genetic
Trastuzumab
Treatment Outcome

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Biomarkers, Tumor
RNA, Small Interfering
Phosphatidylinositol 3-Kinases
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
ERBB2 protein, human
Receptor, ErbB-2
PTEN Phosphohydrolase
PTEN protein, human
Trastuzumab