Abstract 4711: The role ERK1/2 and Androgen Receptor phosphorylation at serine 81 in the progression from hormone naive to castrate resistant prostate cancer
Authors: Edwards Joanne , McCall Pamela , Adams Claire , Mukherjee Rono , Orange Clare , Seywright Morag , Underwood Mark 
Published: February 2011

Prostate cancer incidence in the UK is approximately 35,500 cases per year and the second most common cause of male cancer-specific death. The high mortality rate associated with prostate cancer is attributed to the development of castrate resistance prostate cancer (CRPC). Following the development of CRPC there are few therapeutic options with the mean survival period being only 18-24 months. Cell line studies implement ERK1/2 activation in the transition from hormone naïve prostate cancer (HNPC) to CRPC. Recent evidence suggests that ERK kinase activation induces phosphorylation of AR at Serine 81 (AR81) to stimulate prostate cancer cell growth and induce PSA expression (Shigemura K et al Prostate 2009, 69(9) 949-955). This data suggests that the ERK kinase pathway may provide a novel therapeutic target for treatment of CRPC

The aim of the current study was to investigate if the relationship between the AR and ERK1/2 is upheld in clinical prostate cancer specimens. A cohort of 55 patients with matched HNPC and CRPC tissue was established with full clinical follow-up. Immunohistochemistry was employed to assess expression of AR, AR81, ERK1/2 and phosphorylated ERK1/2 (pERK).

All 55 patients in the cohort were diagnosed with HNPC and subsequently progressed to CRPC. The median age at diagnosis was 70(66-73), median Gleason sum at diagnosis was 8(6-9) and median time to biochemical relapse was 2.3 years. Mean follow-up was 7.5 (4.3-11.7) years, 4 patients were alive at last follow-up, 35 patients died of their disease and 16 patients died of other causes.

In the transition of HNPC to CRPC 8% of patients exhibited an increase in AR81 expression and 20% exhibited an increase in ERK1/2 expression.

PSA at diagnosis (p=0.034) and high pERK expression in HNPC (p=0.03) were associated with shorter time to biochemical relapse. A negative correlation between AR and ERK1/2 expression was observed in HNPC (R2=-0.383, p=0.004), but no association with AR81 and ERK1/2 or pERK was observed in this stage of disease.

Gleason sum (p=0.009), presence of metastasis at diagnosis (p=0.0002), presence of metastasis at relapse (p=0.003) and high ERK1/2 expression in CRPC (p=0.003) were associated with shorter disease specific survival. In CRPC no correlations were observed between AR or AR81 and ERK1/2 or pERK. AR81 expression did however positively correlate with proliferation index as assessed by Ki67 expression (R2=0.339, p=0.025). Combined expression of AR81 and ERK1/2 resulted in a significantly shorter disease specific survival. Whereas, expression of these protein alone (4.2 years vs. 5.4 years) or not at all (7.2 years) resulted in a longer disease specific survival p=0.0006.

In conclusion, although no correlations with AR81 and ERK1/2 or pERK were observed in the current study, high expression of AR81 and ERK1/2 combined had a synergistic effect of decreased disease specific survival.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4711.