Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells.

Martuza Sarwar,Nigel P Mongan,Jun Luo,Brian Robinson,Athanasios Simoulis,Heather Johnsson,Julius Semenas,Per-Anders Abrahamsson,Jenny L Persson,Anette Gjörloff Wingren,Regina Miftakhova,David M Heery,Nishtman Dizeyi

doi:10.18632/oncotarget.11757

Abstract

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1α and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

Highlights

Considerable progress is being made to improve therapy of prostate cancer (PCa), one-third of treated PCa patients will experience disease recurrence and will progress into castration-resistant PCa (CRPC), which are no www.impactjournals.com/oncotarget longer responsive to anti-androgen therapies [1,2,3,4]
A second tissue microarrays (TMAs) that contained biopsies of begin prostate hyperplasia (BPH) and cancer tissues from 48 PCa patients was examined for ARV7 and PIP5K1α expression
Increasing evidence suggests that AR-V7 is involved in development of CRPC, bone metastasis and resistance to enzalutamide[5, 7, 8]

Summary

Introduction

Considerable progress is being made to improve therapy of PCa, one-third of treated PCa patients will experience disease recurrence and will progress into castration-resistant PCa (CRPC), which are no www.impactjournals.com/oncotarget longer responsive to anti-androgen therapies [1,2,3,4]. One mechanism of resistance to antiandrogen treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is ARV7 [5,6,7]. Enzalutamide is beneficial for patients with metastatic CRPC, giving an increasing in survival [11, 12], a rapid development of resistance in PCa patients to enzalutamide treatment remain to be a major clinical challenge [11]. The increased level of AR-V7 transcript was detected in circulating tumor cells from PCa patients who developed enzalutamide resistance [13]. The AR-V7-mediated cellular mechanisms in resistance to enzalutamide remain poorly understood

Methods

Results

Conclusion