The AKT inhibitor triciribine in combination with paclitaxel has order-specific efficacy against Zfp217-induced breast cancer chemoresistance

Christopher D. Suarez, Junmin Wu, Sunil S. Badve, Joseph A. Sparano, William Kaliney, Laurie E. Littlepage

Research output: Contribution to journalArticle

Abstract

We previously identified the transcription factor ZNF217 (human) / Zfp217 (mouse) as an oncogene and prognostic indicator of reduced survival, increased metastasis, and reduced response to therapy in breast cancer patients. Here we investigated the role of Zfp217 in chemotherapy resistance. Preclinical animal models of Zfp217 overexpression were treated with a combination therapy of the microtubule inhibitor epothilone B, doxorubicin (Adriamycin), and cyclophosphamide (EAC). Tumors overexpressing Zfp217 increased their tumor burden compared to control tumors after treatment and accumulated a mammary gland progenitor cell population (K8+K14+). To overcome this chemoresistance after ZNF217 overexpression, we treated tumors ± Zfp217 overexpression with paclitaxel and triciribine, a nucleoside analog and AKT inhibitor that kills cells that overexpress ZNF217. Treatment order critically impacted the efficacy of the therapy. Combination treatment of triciribine followed by paclitaxel (TCN→PAC) inhibited tumor burden and increased survival in tumors that overexpressed Zfp217, whereas single agent or combination treatment in the reverse order (PAC→TCN) did not improve response. Analysis of these tumors and patient-derived tumor xenograft tumors treated with the same therapies suggested that Zfp217 overexpression in tumors contributes both to decreased microvessel density and vessel maturity, while TCN→PAC tumors overexpressing Zfp217 showed improved vessel maturity. All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.

Original languageEnglish (US)
Pages (from-to)108534-108547
Number of pages14
JournalOncotarget
Volume8
Issue number65
DOIs
StatePublished - Jan 1 2017

Keywords

  • Chemoresistance
  • Microvessel density
  • Patient-derived tumor xenograft
  • Triciribine
  • Zfp217/ZNF217

ASJC Scopus subject areas

  • Oncology

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