Androgen receptor (AR) plays a critical role in progression of prostate cancer. We have recently demonstrated that Ack1 (also known as TNK2) regulates AR Tyr267-phosphorylation within the transactivation domain. While AR transcriptional activation by multiple tyrosine kinases is emerging as an alternate mode of AR activation, the precise role of Ack1 mediated AR Tyr267- phosphorylation in AR recruitment to the androgen responsive enhancers (ARE) and androgen- independent AR-responsive gene transcription is not fully understood. In this grant proposal we demonstrate that activated Ack1(pTyr284-Ack1) expression is upregulated as prostate cancer progresses and this activation is inversely correlated with the survival of prostate cancer patients. Since Ack1 regulates androgen-independent AR activity by its phosphorylation at Tyr267, we generated antibodies that specifically recognize pTyr267-AR. Neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens e.g. bicalutamide/casodex and flutamide. However, a small molecule inhibitor of Ack1, 4-Amino-5,6- biaryl-furo[2,3-d]pyrimidine (YL3-026) not only inhibited Ack1 activation, but was able to suppress pTyr267-AR phosphorylation, binding to PSA, NKX3.1 and TMPRS2 promoters and inhibit AR transcription activity as seen by significant decrease in PSA gene expression. Our evidence indicates that targeting Ack1 kinase in prostate cancer patients could therefore be highly effective therapeutic strategy. In this proposal we will determine how AR Tyr267- phosphorylation regulates Androgen-Independent growth. Further, we will examine the ability of Ack1 inhibitor, YL3-026, to suppress androgen-independent transcription and xenograft tumor formation. Moreover, we will assess the ability of Ack1 inhibitor YL3-026 to suppress AR Tyr267-phosphorylation and prostatic intraepithelial neoplasia (PINs) formation in Prob-Ack1 transgenic mice.
Ack1: A critical regulator of hormonre-refractory prostate cancer A Hormone refractory prostate cancer is a significant cause of cancer death among American men. Here we demonstrate that that activated Ack1 expression is upregulated as prostate cancer progresses to androgen independence and this activation is inversely correlated with the survival of prostate cancer patients (n=267 patients). Using specific antibodies against Tyr267-phosphorylated AR (pTyr267-AR), we have shown that transcriptional activation of pTyr267-AR was unaffected by anti-androgens e.g. bicalutamide/casodex and flutamide. To precisely understand role of Ack1 in AR transcriptional activation in absence of androgens, we synthesized 4-Amino-5,6-biaryl-furo[2,3- d]pyrimidine (termed here as YL3-026). YL3-026 not only inhibited Ack1 activation, but was able to suppress pTyr267-AR phosphorylation, its binding to PSA, NKX3.1 and TMPRS2 promoters and inhibit AR transcription activity as seen by significant decrease in PSA gene expression. In this proposal we will identify a set of genes that are regulated by pTyr267-AR. Further, we shall assess effect of YL3-026 on formation of prostatic intraepithelial neoplasia in transgenic mice. Overall, this proposal would allow us to examine whether targeting Ack1 kinase in prostate cancer patients is an appropriate therapeutic strategy.
|Lawrence, Harshani R; Mahajan, Kiran; Luo, Yunting et al. (2015) Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. J Med Chem 58:2746-63|
|Mahajan, K; Mahajan, N P (2015) ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene 34:4162-7|
|Mahajan, Kiran; Mahajan, Nupam P (2015) Cross talk of tyrosine kinases with the DNA damage signaling pathways. Nucleic Acids Res 43:10588-601|
|Mahajan, Kiran N; Mahajan, Nupam P (2014) AKT goes cycling. Cancer Control 21:239-41|
|Mahajan, Kiran; Lawrence, Harshani R; Lawrence, Nicholas J et al. (2014) ACK1 tyrosine kinase interacts with histone demethylase KDM3A to regulate the mammary tumor oncogene HOXA1. J Biol Chem 289:28179-91|
|Mahajan, Kiran; Mahajan, Nupam P (2013) WEE1 tyrosine kinase, a novel epigenetic modifier. Trends Genet 29:394-402|
|Linderoth, Emma; Pilia, Giulia; Mahajan, Nupam P et al. (2013) Activated Cdc42-associated kinase 1 (Ack1) is required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor recruitment to lipid rafts and induction of cell death. J Biol Chem 288:32922-31|
|Mahajan, Kiran; Mahajan, Nupam P (2013) ACK1 tyrosine kinase: targeted inhibition to block cancer cell proliferation. Cancer Lett 338:185-92|
|Mahajan, Kiran; Coppola, Domenico; Rawal, Bhupendra et al. (2012) Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer. J Biol Chem 287:22112-22|
|Mahajan, Kiran; Coppola, Domenico; Chen, Y Ann et al. (2012) Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. Am J Pathol 180:1386-93|
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