title: Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response.
abstract: BACKGROUND
  Approximately 15%-20% of all diagnosed breast cancers are characterized by amplified and overexpressed HER2 (= ErbB2). These breast cancers are aggressive and have a poor prognosis. Although improvements in treatment have been achieved after the introduction of trastuzumab and lapatinib, many patients do not benefit from these drugs. Therefore, in-depth understanding of the mechanisms behind the treatment responses is essential to find alternative therapeutic strategies.
  
  
  METHODS
  Thirteen HER2 positive breast cancer cell lines were screened with 22 commercially available compounds, mainly targeting proteins in the ErbB2-signaling pathway, and molecular mechanisms related to treatment sensitivity were sought. Cell viability was measured, and treatment responses between the cell lines were compared. To search for response predictors and genomic and transcriptomic profiling,PIK3CAmutations andPTENstatus were explored and molecular features associated with drug sensitivity sought.
  
  
  RESULTS
  The cell lines were divided into three groups according to the growth-retarding effect induced by trastuzumab and lapatinib. Interestingly, two cell lines insensitive to trastuzumab (KPL4 and SUM190PT) showed sensitivity to an Akt1/2 kinase inhibitor. These cell lines had mutation inPIK3CAand loss ofPTEN, suggesting an activated and druggable Akt-signaling pathway. Expression levels of five genes (CDC42,MAPK8,PLCG1,PTK6, andPAK6) were suggested as predictors for the Akt1/2 kinase-inhibitor response.
  
  
  CONCLUSIONS
  Targeting the Akt-signaling pathway shows promise in cell lines that do not respond to trastuzumab. In addition, our results indicate that several molecular features determine the growth-retarding effects induced by the drugs, suggesting that parameters other than HER2 amplification/expression should be included as markers for therapy decisions.
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital; KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jernström
authors.affiliation: Misvik Biology Oy, Turku.
authors.forename: Vesa
authors.initials: V
authors.lastname: Hongisto
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital; KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Suvi-Katri
authors.initials: SK
authors.lastname: Leivonen
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital.
authors.forename: Eldri Undlien
authors.initials: EU
authors.lastname: Due
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital.
authors.forename: Dagim Shiferaw
authors.initials: DS
authors.lastname: Tadele
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki; Medisapiens, Helsinki, Finland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: VTT Technical Research Centre of Finland, Turku, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.affiliation: KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø.
authors.forename: Gunhild Mari
authors.initials: GM
authors.lastname: Mælandsmo
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital; Department of Research, Vestre Viken Hospital Trust, Drammen, Norway.
authors.forename: Kristine Kleivi
authors.initials: KK
authors.lastname: Sahlberg
keywords: ErbB2; drug screening; gene expression; pharmacogenomics; predictors