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Updated: Mar 13, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Combination effect of therapies targeting the PI3K- and AR-signaling pathways in prostate cancer
Shalini Singh Yadav1, Jinyi Li1, Jennifer A Stockert1
1Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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.
Insights
Combination therapy for prostate cancer (PCa) shows promise. Combining androgen receptor (AR) inhibitors with PI3K-pathway inhibitors, like BKM120, effectively induces cell death and demonstrates significant synergy in PCa cells.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Prostate cancer (PCa) treatments targeting the androgen receptor (AR) and PI3K/AKT/mTOR pathways show limited long-term benefits as single agents.
- Complex cross-talk between AR and PI3K pathways may hinder efficacy of monotherapies.
- Combination therapy is a promising strategy to overcome resistance and enhance treatment outcomes in PCa.
Purpose of the Study:
- To systematically evaluate the synergistic effects of two-drug combinations involving AR antagonists and PI3K-pathway inhibitors in various PCa cell lines.
- To identify optimal drug combinations for maximizing therapeutic benefit in prostate cancer treatment.
- To investigate the efficacy of combining AR-targeted therapy with PI3K/RTK/mTOR pathway inhibitors.
Main Methods:
- Utilized multiple prostate cancer cell lines (LNCaP, VCaP, 22Rv1, PC3, Du145) for drug combination studies.
- Assessed drug synergy using growth curve analysis and confirmed with Western blot analysis.
- Tested combinations including MDV3100 (AR antagonist), BKM120 (PI3K inhibitor), TKI258 (pan RTK inhibitor), and RAD001 (mTOR inhibitor).
Main Results:
- Strong synergy observed when AR-positive cells were treated with MDV3100 combined with PI3K-pathway inhibitors (TKI258, BKM120, RAD001).
- The combination of MDV3100 and BKM120 was most effective in inducing cell death.
- BKM120 and TKI258 combination showed high sensitivity across all tested cell lines, regardless of androgen sensitivity.
- BKM120+TKI258 demonstrated superior synergy compared to BKM120+RAD001 or RAD001+TKI258.
- BKM120 also showed synergy when combined with the chemotherapy drug cabazitaxel.
Conclusions:
- Combination of AR inhibitors and PI3K-pathway inhibitors is highly synergistic in prostate cancer.
- The combination of BKM120 and TKI258 is a potent synergistic pairing for dual PI3K-pathway targeting.
- BKM120 combined with chemotherapy agent cabazitaxel also exhibits synergistic effects.
- No antagonistic effects were observed for any of the tested drug combinations, supporting their potential clinical utility.
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