Oncotarget

Research Papers:

Combination effect of therapies targeting the PI3K- and AR-signaling pathways in prostate cancer

Shalini Singh Yadav _, Jinyi Li, Jennifer A. Stockert, James O’Connor, Bryan Herzog, Cordelia Elaiho, Matthew D. Galsky, Ashutosh Kumar Tewari and Kamlesh Kumar Yadav

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Oncotarget. 2016; 7:76181-76196. https://doi.org/10.18632/oncotarget.12771

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Abstract

Shalini Singh Yadav1,*, Jinyi Li1,*, Jennifer A. Stockert1, James O’Connor1, Bryan Herzog1, Cordelia Elaiho1, Matthew D. Galsky1,2, Ashutosh Kumar Tewari1, Kamlesh Kumar Yadav1

1Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

2Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

*These authors have contributed equally to this work

Correspondence to:

Shalini Singh Yadav, email: shalini.singh@mountsinai.org

Ashutosh Kumar Tewari, email: ash.tewari@mountsinai.org

Kamlesh Kumar Yadav, email: kamlesh.yadav@mountsinai.org

Keywords: prostate cancer, drug-resistance, drug combination, synergy, antagonism

Received: January 28, 2016    Accepted: October 01, 2016    Published: October 20, 2016

ABSTRACT

Several promising targeted-therapeutics for prostate cancer (PCa), primarily affecting the androgen receptor (AR) and the PI3K/AKT/mTOR-pathway, are in various phases of development. However, despite promise, single-agent inhibitors targeting the two pathways have not shown long-term benefits, perhaps due to a complex compensatory cross talk that exists between the two pathways. Combination therapy has thus been proposed to maximize benefit. We have carried out a systematic study of two-drug combination effect of MDV3100 (AR antagonist), BKM120 (PI3K inhibitor), TKI258 (pan RTK inhibitor) and RAD001 (mTOR inhibitor) using various PCa cell lines. We observed strong synergy when AR-positive cells are treated with MDV3100 in combination with any one of the PI3K-pathway inhibitors: TKI258, BKM120, or RAD001. Growth curve based synergy determination combined with Western blot analysis suggested MDV3100+BKM120 to be the most effective in inducing cell death in such conditions. In the case of dual targeting of the PI3K-pathway BKM120+TKI258 combination displayed exquisite sensitivity in all the 5 cell lines tested irrespective of androgen sensitivity, (LNCaP, VCaP, 22Rv1, PC3 and Du145). The effect of blockade with BKM120+TKI258 in PC3 cells was similar to a combination of BKM120 with chemotherapy drug cabazitaxel.

Taken together, our observation supports earlier observations that a combination of AR-inhibitor and PI3K-inhibitor is highly synergistic. Furthermore, combining BKM120 with TKI258 has better synergy than BKM120+RAD001 or RAD001+TKI258 in all the lines, irrespective of androgen sensitivity. Finally, BKM120 also displayed synergy when combined with chemotherapy drug cabazitaxel. No antagonism however was observed with any of the drug combinations.


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