| Summary: | Sandra Jernström,1,2 Vesa Hongisto,3 Suvi-Katri Leivonen,1,2 Eldri Undlien Due,1 Dagim Shiferaw Tadele,1 Henrik Edgren,4,5 Olli Kallioniemi,4 Merja Perälä,6 Gunhild Mari Mælandsmo,2,7,8 Kristine Kleivi Sahlberg,1,9 1Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, 2KG Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway; 3Misvik Biology Oy, Turku, 4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, 5Medisapiens, Helsinki, Finland, 6VTT Technical Research Centre of Finland, Turku, Finland; 7Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 8Institute of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, 9Department of Research, Vestre Viken Hospital Trust, Drammen, Norway 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. Materials and 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, PIK3CA mutations and PTEN status 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 in PIK3CA and loss of PTEN, suggesting an activated and druggable Akt-signaling pathway. Expression levels of five genes (CDC42, MAPK8, PLCG1, PTK6, and PAK6) were suggested as predictors for the Akt1/2 kinase-inhibitor response. Conclusion: 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. Keywords: ErbB2, drug screening, gene expression, pharmacogenomics, predictors
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