A group of researchers from the British Columbia Cancer Agency have demonstrated that targeting the mTOR pathway, and the full-length androgen receptor (FL-AR) and androgen receptor variants (AR-Vs) together, is effective at inhibiting castration-resistant prostate cancer (CRPC) cell growth in vitro and in vivo.

In vitro investigations using enzalutamide-resistant and androgen-independent LNCaP95 cells revealed that combined treatment with BEZ235 (an inhibitor of PI3K and mTOR) and EPI-002 (an AF-1 antagonist, which blocks the activity of FL-AR and truncated AR species) significantly reduced cell growth compared with each as a monotherapy. The same was also true of everolimus in combination with EPI-002. Treatment with BEZ235 in the absence of androgen increased levels of FL-AR, and UBE2C protein levels were reduced by EPI-002. BEZ235 monotherapy significantly increased the luciferase activity of PSA, ARR3 and probasin in androgen-treated cells, an effect that was blocked by both EPI-002 and enzalutamide. BEZ235 treatment in the presence of androgen did not increase FL-AR activity, but in LNCaP cells it significantly inhibited AR-N-terminal domain (AR-NTD) transactivation.

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EPI-002 and enzalutamide reduced the expression of KLK3, TMPRSS2 and FKBP5, which are FL-AR-regulated genes. BEZ235 increased androgen-induced and androgen-independent expression of PSA and in the absence of androgen EPI-002, but not enzalutamide, blocked this effect. Treatment with BEZ235 also induced a twofold increase in AR-V7 levels in the absence of androgen; this increase was blocked by treatment with EPI-002.

In vivo, castrated mice with xenografted tumours treated with a combination of BEZ235 and EPI-002 had significantly reduced tumour volumes compared with mice given either as a monotherapy.

These results indicate that targeting both the mTOR pathway and the AR-NTD to inhibit FL-AR and AR-Vs could have a therapeutic advantage in treating CRPC.