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.

Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy

“…In this study, we combined Ar silencing with AZD5363 blockade to target both AR and PI3K/AKT and, indeed, the agents significantly inhibited tumor progression, resulting in an OS benefit after development of CRPC. This study supports other studies and emphasizes the importance of concomitant inhibition of AR and AKT to enhance antitumor responses of PCa (23,24,58,59). Although we showed a significant improvement in treatment response, tumors invariably continued to grow, indicating that other mechanisms are being coordinated to promote tumor survival.…”

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

“…S4C), would seemingly result in better clinical benefits. Indeed, preclinical models inhibiting both AR and the PI3K/Akt axis show promising results (Carver et al 2011;Toren et al 2015;Yadav et al 2016). However, clinical pilot studies on anti-androgens and PI3K/Akt/mTOR inhibitors show high proportions of severe adverse effects and high rates of treatment discontinuation, with no clear indication that the PI3K/Akt/mTOR inhibitors reached and inhibited their targets in PCa tissues (Armstrong et al 2017;Massard et al 2017;Wei et al 2017).…”

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

“…Combining PI3K/mTOR and other pathway inhibitors or glucocorticoids may be an approach to overcome the therapeutic-resistance of certain cancers [ 132 – 134 ]. Targeting the PI3K and androgen receptor pathways may be an approach to treat therapy-resistant prostate cancer [ 135 , 136 ].…”