title: A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.
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.
authors.affiliation: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Berns
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Mandy
authors.initials: M
authors.lastname: Madiredjo
authors.forename: E Marielle
authors.initials: EM
authors.lastname: Hijmans
authors.forename: Karin
authors.initials: K
authors.lastname: Beelen
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Marc J
authors.initials: MJ
authors.lastname: van de Vijver
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: 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
chemical_list: 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