A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.
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.
Berns
Katrien
K
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Horlings
Hugo M
HM
Hennessy
Bryan T
BT
Madiredjo
Mandy
M
Hijmans
E Marielle
EM
Beelen
Karin
K
Linn
Sabine C
SC
Gonzalez-Angulo
Ana Maria
AM
Stemke-Hale
Katherine
K
Hauptmann
Michael
M
Beijersbergen
Roderick L
RL
Mills
Gordon B
GB
van de Vijver
Marc J
MJ
Bernards
René
R
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D018579:Patient Selection; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014161:Transduction, Genetic; D000068878:Trastuzumab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human