Therapeutic potential of CDK inhibitor NU2058 in androgen-independent prostate cancer

Abstract

Antiandrogens are initially effective in controlling prostate cancer (CaP), the second most common cancer in men, but resistance, associated with the loss of androgenregulated cell cycle control, is a major problem. At present there is no effective treatment for androgen-independent prostate cancer (AIPC). Cellular proliferation is driven by cyclin-dependent kinases (CDKs) with kinase inhibitors (for example, p27) applying the breaks. We present the first investigation of the therapeutic potential of CDK inhibitors, using the guanine-based CDK inhibitor NU2058 (CDK2 IC 50 ¼ 17 lM, CDK1 IC 50 ¼ 26 lM), in comparison with the antiandrogen bicalutamide (Casodex) in AIPC cells. A panel of AIPC cells was found to be resistant to Casodex-induced growth inhibition, but with the exception of PC3 (GI 50 ¼ 38 lM) and CWR22Rv1 (GI 50 ¼ 46 lM) showed similar sensitivity to NU2058 (GI 50 ¼ 10-17 lM) compared to androgen-sensitive LNCaP cells (GI 50 ¼ 15 lM). In LNCaP cells and their Casodex-resistant derivative, LNCaP-cdxR, growth inhibition by NU2058 was accompanied by a concentrationdependent increase in p27 levels, reduced CDK2 activity and pRb phosphorylation, a decrease in early gene expression and G1 cell cycle phase arrest in both cell lines. In response to Casodex, there were similar observations in LNCaP cells (GI 50 ¼ 673 lM Casodex) but not in LNCaP-cdxR cells (GI 50 ¼ 2475 lM Casodex).

Genomic alterations in plasma DNA from patients with metastasized prostate cancer receiving abiraterone or enzalutamide

“…z-score >5. Several of these pathways have possible therapeutic implications in prostate cancer, including the use of PARP inhibitors in the presence of DNA repair pathway deficiencies 34, 37 , PI3 kinase pathway inhibitors in the presence of activating mutations or genomic alterations 38 or cyclin-dependent kinase (CDK) inhibitors 39 .…”

Upregulated FGFR1 expression is associated with the transition of hormone-naive to castrate-resistant prostate cancer

“…CdxR-LNCaP cells were generated and maintained as described previously (Halkidou et al , 2003; Rigas et al , 2007). Anti-FGFR1 antibody (Flg (C-15)) was obtained from Santa Cruz Biotechnologies (Santa Cruz, CA, USA).…”

Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2

“…The major reason is that the low specificity exhibited by these inhibitors often results in off-target effects, thus ultimately limiting their therapeutic efficiencies [27]. Therefore, the second generation of ATP-competitive inhibitors are more potent, and specific ligands for CDKs such as P276-00 [28], AT7519 [29] and NU2058 [30] (Figure 1), have been developed and assessed in preclinical and clinical trials. For instance, a highly specific inhibitor of CDK2 (IC 50 = 10 nM) [31], P276-00, exhibits potent anti-proliferative effects against several human tumor cells [32], and is undergoing phase I–II clinical trials [33].…”