Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity.
BACKGROUND
Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. Recently, tyrosine kinase Ack1 has been shown to regulate AR activity by phosphorylating it at tyrosine 267 and this event was shown to be critical for AIPC growth. However, whether a small molecule inhibitor that can mitigate Ack1 activation is sufficient to abrogate AR activity on AR regulated promoters in androgen-depleted environment is not known.


METHODS
We have generated two key resources, antibodies that specifically recognize pTyr267-AR and synthesized a small molecule inhibitor of Ack1, 4-amino-5,6-biaryl-furo[2,3-d]pyrimidine (named here as AIM-100) to test whether AIM-100 modulates ligand-independent AR activity and inhibits prostate cell growth.


RESULTS
Prostate tissue microarray analysis indicates that Ack1 Tyr284 phosphorylation correlates positively with disease progression and negatively with the survival of prostate cancer patients. Interestingly, neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens in activated Ack1 expressing or EGF stimulated prostate cells. However, the Ack1 inhibitor, AIM-100, not only inhibited Ack1 activation but also able to suppress pTyr267-AR phosphorylation, binding of AR to PSA, NKX3.1, and TMPRSS2 promoters, and inhibit AR transcription activity.


CONCLUSIONS
Ack1 Tyr284 phosphorylation is prognostic of progression of prostate cancer and inhibitors of Ack1 activity could be novel therapeutic agents to treat AIPC.
Mahajan
Kiran
K
Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA.
Challa
Sridevi
S
Coppola
Domenico
D
Lawrence
Harshani
H
Luo
Yunting
Y
Gevariya
Harsukh
H
Zhu
Weiwei
W
Chen
Y Ann
YA
Lawrence
Nicholas J
NJ
Mahajan
Nupam P
NP
D000595:Amino Acid Sequence; D000728:Androgens / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000917:Antibody Formation; D045744:Cell Line, Tumor; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010748:Phosphopeptides / Q000737:chemistry; D011470:Prostatic Hyperplasia / Q000150:complications; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011944:Receptors, Androgen / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015996:Survival Rate
D000728:Androgens; D010748:Phosphopeptides; D011944:Receptors, Androgen; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human