The AKT inhibitor triciribine in combination with paclitaxel has order-specific efficacy against Zfp217-induced breast cancer chemoresistance
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Christopher D. Suarez1,2, Junmin Wu1,2, Sunil S. Badve3, Joseph A. Sparano4, William Kaliney2 and Laurie E. Littlepage1,2
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
2Harper Cancer Research Institute, South Bend, IN 46617, USA
3Indiana University School of Medicine, Indianapolis, IN 46202, USA
4Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Laurie E. Littlepage, email: [email protected]
Keywords: Zfp217/ZNF217; triciribine; chemoresistance; patient-derived tumor xenograft; microvessel density
Received: May 22, 2016 Accepted: February 02, 2017 Published: July 17, 2017
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.
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