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 Mills, Marc J. van de Vijver, René Bernards

Research output: Contribution to journalArticle

1119 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)395-402
Number of pages8
JournalCancer Cell
Volume12
Issue number4
DOIs
StatePublished - Oct 16 2007
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Breast Neoplasms
Patient Participation
RNA Interference
Cell Culture Techniques
Biomarkers
Mutation
Trastuzumab
Therapeutics
Pharmaceutical Preparations
Genes

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Berns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., ... Bernards, R. (2007). A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer. Cancer Cell, 12(4), 395-402. https://doi.org/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. / 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; van de Vijver, Marc J.; Bernards, René.

In: Cancer Cell, Vol. 12, No. 4, 16.10.2007, p. 395-402.

Research output: Contribution to journalArticle

Berns, K, Horlings, HM, Hennessy, BT, Madiredjo, M, Hijmans, EM, Beelen, K, Linn, SC, Gonzalez-Angulo, AM, Stemke-Hale, K, Hauptmann, M, Beijersbergen, RL, Mills, G, van de Vijver, MJ & Bernards, R 2007, 'A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer', Cancer Cell, vol. 12, no. 4, pp. 395-402. https://doi.org/10.1016/j.ccr.2007.08.030
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 ; van de Vijver, Marc J. ; Bernards, René. / A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer. In: Cancer Cell. 2007 ; Vol. 12, No. 4. pp. 395-402.
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