Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy.
The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated AR(W741L/C) mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of AR(W741L) highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, AR(W741L) transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients.
AstraZeneca, Innovative Medicines, Discovery Sciences, Cambridge Science Park, Cambridge, CB4 0WG, UK.
Daniel
D
O'Neill
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Dominic
D
Jones
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Mark
M
Wade
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
James
J
Grey
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Sirintra
S
Nakjang
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Wenrui
W
Guo
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
David
D
Cork
AstraZeneca, Innovative Medicines, Discovery Sciences, Cambridge Science Park, Cambridge, CB4 0WG, UK.
Barry R
BR
Davies
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Steve R
SR
Wedge
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Craig N
CN
Robson
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Luke
L
Gaughan
D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000099184:Serum-Glucocorticoid Regulated Kinases
D000726:Androgen Antagonists; D000813:Anilides; D001549:Benzamides; D017874:Immediate-Early Proteins; D009570:Nitriles; D010669:Phenylthiohydantoin; D017346:Protein Serine-Threonine Kinases; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D000099184:Serum-Glucocorticoid Regulated Kinases; C410798:AR protein, human; C540278:enzalutamide; C053541:bicalutamide
SGK1; androgen receptor; anti-androgen-resistance; mutation; prostate cancer