title: Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death.
abstract: A critical first step in the personalized approach to cancer treatment is the identification of activated oncogenes that drive each tumor. The Identification of driver oncogenes on a patient-by-patient basis is complicated by the complexity of the cancer genome and the fact that a particular genetic alteration may serve as a driver event only in a subset of tumors that harbor it. In this study, we set out to identify the complete set of functional oncogenes in a small panel of breast cancer cell lines. The cell lines in this panel were chosen because they each contain a known receptor tyrosine kinase (RTK) oncogene. To identify additional drivers, we integrated functional genetic screens with copy number and mutation analysis, and cancer genome knowledge databases. The resulting functional oncogene signatures were able to predict responsiveness of cell lines to targeted inhibitors. However, as single agents, these drugs had little effect on clonogenic potential. By contrast, treatment with drug combinations that targeted multiple oncogenes in the signatures, even at very low doses, resulted in the induction of apoptosis and striking synergistic effects on clonogenicity. In particular, targeting a driver oncogene that mediates AKT phosphorylation in combination with targeting the anti-apoptotic BCL2L1 protein had profound effects on cell viability. Importantly, because the synergistic induction of cell death was achieved using low levels of each individual drug, it suggests that a therapeutic strategy based on this approach could avoid the toxicities that have been associated with the combined use of multiple-targeted agents.
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Guest
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Kratche
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Irish
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wilson
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Ramsi
authors.initials: R
authors.lastname: Haddad
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: Department of Public Health Science, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ethier
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015513:Oncogene Proteins; D054852:Small Molecule Libraries; D020794:Receptor Protein-Tyrosine Kinases
keywords: AKT; BCL2L1; FGFR; breast cancer; functional genomics