Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death

Stephen T. Guest, Zachary R. Kratche, Jonathan C. Irish, Robert C. Wilson, Ramsi Haddad, Joe Gray, Elizabeth Garrett-Mayer, Stephen P. Ethier

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 multipletargeted agents.

Original languageEnglish (US)
Pages (from-to)36138-36153
Number of pages16
JournalOncotarget
Volume7
Issue number24
DOIs
StatePublished - 2016

Fingerprint

Oncogenes
Cell Death
Breast Neoplasms
Neoplasms
Cell Line
Therapeutics
Genome
Apoptosis Regulatory Proteins
Receptor Protein-Tyrosine Kinases
Drug Combinations
Pharmaceutical Preparations
Cell Survival
Phosphorylation
Databases
Apoptosis
Mutation

Keywords

  • AKT
  • BCL2L1
  • Breast cancer
  • FGFR
  • Functional genomics

ASJC Scopus subject areas

  • Oncology

Cite this

Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death. / Guest, Stephen T.; Kratche, Zachary R.; Irish, Jonathan C.; Wilson, Robert C.; Haddad, Ramsi; Gray, Joe; Garrett-Mayer, Elizabeth; Ethier, Stephen P.

In: Oncotarget, Vol. 7, No. 24, 2016, p. 36138-36153.

Research output: Contribution to journalArticle

Guest, ST, Kratche, ZR, Irish, JC, Wilson, RC, Haddad, R, Gray, J, Garrett-Mayer, E & Ethier, SP 2016, 'Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death', Oncotarget, vol. 7, no. 24, pp. 36138-36153. https://doi.org/10.18632/oncotarget.9147
Guest, Stephen T. ; Kratche, Zachary R. ; Irish, Jonathan C. ; Wilson, Robert C. ; Haddad, Ramsi ; Gray, Joe ; Garrett-Mayer, Elizabeth ; Ethier, Stephen P. / Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death. In: Oncotarget. 2016 ; Vol. 7, No. 24. pp. 36138-36153.
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