AR-V7 & Xtandi resistance. PIP5K1α & ISA-2011B.

[pjoshea13]

New study below.

International effort: Sweden / U.S. / U.K. / China / Russia.

"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."

So, ISA-2011B might ultimately be used to restore sensitivity to Xtandi, or to prevent AR-V7 resistance.

-Patrick

ncbi.nlm.nih.gov/pubmed/275...

Oncotarget. 2016 Aug 31. doi: 10.18632/oncotarget.11757. [Epub ahead of print]

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

Sarwar M1, Semenas J1,2, Miftakhova R1,3,2, Simoulis A4, Robinson B5, Wingren AG6, Mongan NP7, Heery DM8, Johnsson H9, Abrahamsson PA10, Dizeyi N10, Luo J11, Persson JL1,2.

Author information

1Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.

2Department of Molecular Biology, Umeå University, Sweden.

3Department of Genetics, Kazan Federal University, Kazan, Russia.

4Department of Clinical Pathology and Cytology, Skåne University Hospital, Malmö, Sweden.

5Department of Pathology, Weill Cornell Medical College, New York, NY, USA.

6Faculty of Health and Society, Department of Biomedical Science, Malmö University, Malmö, Sweden.

7Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Sciences, University of Nottingham, Nottingham, United Kingdom.

8School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.

9Department of Bio-diagnosis, Beijing Institute of Basic Medical Sciences, Beijing, China.

10Division of Clinical Urology, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.

11Department of Urology, the James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

KEYWORDS:

AR-V7; PIP5K1α; Prostate cancer metastasis; enzalutamide resistance; lipid kinase inhibitor

PMID: 27588408 DOI: 10.18632/oncotarget.11757

[PubMed - as supplied by publisher]