title: Combination effect of therapies targeting the PI3K- and AR-signaling pathways in prostate cancer.
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.
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Shalini Singh
authors: SS
authors: Yadav
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Jinyi
authors: J
authors: Li
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Jennifer A
authors: JA
authors: Stockert
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: James
authors: J
authors: O'Connor
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Bryan
authors: B
authors: Herzog
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Cordelia
authors: C
authors: Elaiho
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.|Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Matthew D
authors: MD
authors: Galsky
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ashutosh Kumar
authors: AK
authors: Tewari
authors: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Kamlesh Kumar
authors: KK
authors: Yadav
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D019869:Phosphatidylinositol 3-Kinases
keywords: antagonism; drug combination; drug-resistance; prostate cancer; synergy