TY - JOUR
T1 - A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer
AU - Berns, Katrien
AU - Horlings, Hugo M.
AU - Hennessy, Bryan T.
AU - Madiredjo, Mandy
AU - Hijmans, E. Marielle
AU - Beelen, Karin
AU - Linn, Sabine C.
AU - Gonzalez-Angulo, Ana Maria
AU - Stemke-Hale, Katherine
AU - Hauptmann, Michael
AU - Beijersbergen, Roderick L.
AU - Mills, Gordon B.
AU - van de Vijver, Marc J.
AU - Bernards, René
N1 - Funding Information:
We thank Jos Beijnen for the gift of trastuzumab for the cell culture experiments, A. Ajouaou and A. Sahin for pathology assistance, R. Pruntel for DNA sequence analysis, and the NKI microarray facility for help with the barcode experiments. This work was supported by a grant from the NIH and the EU grant INTACT.
PY - 2007/10/16
Y1 - 2007/10/16
N2 - 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.
AB - 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=35148885729&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35148885729&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2007.08.030
DO - 10.1016/j.ccr.2007.08.030
M3 - Article
C2 - 17936563
AN - SCOPUS:35148885729
SN - 1535-6108
VL - 12
SP - 395
EP - 402
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -