title: Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer.
abstract: Breast cancer is the second most common cause of cancer-related deaths worldwide among women. Despite several therapeutic options, 15% of breast cancer patients succumb to the disease owing to tumor relapse and acquired therapy resistance. Particularly in triple-negative breast cancer (TNBC), developing effective treatments remains challenging owing to the lack of a common vulnerability that can be exploited by targeted approaches. We have previously shown that tumor cells have different requirements for growth in vivo than in vitro. Therefore, to discover novel drug targets for TNBC, we performed parallel in vivo and in vitro genetic shRNA dropout screens. We identified several potential drug targets that were required for tumor growth in vivo to a greater extent than in vitro. By combining pharmacologic inhibitors acting on a subset of these candidates, we identified a synergistic interaction between EGFR and ROCK inhibitors. This combination effectively reduced TNBC cell growth by inducing cell cycle arrest. These results illustrate the power of in vivo genetic screens and warrant further validation of EGFR and ROCK as combined pharmacologic targets for breast cancer.
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
authors.forename: Sedef
authors.initials: S
authors.lastname: Iskit
authors.affiliation: Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Drug Discovery Research and Screening Services, BioFocus, Darwinweg, Leiden.
authors.forename: Pasi
authors.initials: P
authors.lastname: Halonen
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
authors.forename: Aida
authors.initials: A
authors.lastname: Shahrabi
authors.affiliation: Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Possik
authors.affiliation: Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D054460:rho-Associated Kinases
keywords: EGFR; ROCK; TNBC; in vivo screen; targeted therapy