Evolving therapeutic concepts in prostate cancer based on genome-wide analyses (Review)

Abstract

Treatment of castration resistant prostate cancer (CRPC) continues to represent a major urooncological challenge due to tumor heterogeneity and the inevitable development of therapy resistance. Although androgen deprivation therapy retains an important role in the management of CRPC, recent evidence suggests that a broader spectrum of therapeutic targets may improve patient response and delay development of advanced disease. Genome-wide analyses have identified four major signaling nodes that are most frequently altered in prostate cancer: i) the androgen receptor (AR); ii) the PI3K pathway; iii) the Ras/Raf/MEK/ERK pathway; and iv) the retinoblastoma protein (pRB) signaling pathway. Extensive crosstalk and redundancy exists between these signaling pathways, which underscores the need for combination therapies. There are several novel AR pathway inhibitors currently in clinical use. Clinical trials are being performed on single-agent PI3K inhibitors with some success in tumors with genetically altered PI3K components. MEK/ERK inhibitors are also in clinical trials and the importance of pRB inactivation in prostate cancer is becoming more widely recognized. A greater understanding of the effects of single agent therapy on compensatory signaling pathway activation that can potentially thwart antitumoral responses is urgently needed and will provide additional insight into the mechanism of therapy resistance and how to further delay the progression to lethal disease.

Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

“…4A). MEK-ERK pathway and PI3K-AKT impact multiple aspects of prostate cancer biology (25). PF-03084014 impaired MEK and ERK phosphorylation.…”

PROSTAGLANDIN E2 stimulates cancer‐related phenotypes in prostate cancer PC3 cells through cyclooxygenase‐2

“…Further studies demonstrated that the increasing effect of EGFR on COX‐2 expression was mediated by kinases PI3K and MSK‐1 (the latter previously activated by MAP kinases p38 and Erk1/2). Interestingly, most of the components of the pathway leading to COX‐2 upregulation, such are c‐Src, EGFR, PI3k‐Akt, and Erk1/2, have been suggested to play relevant roles in PC, as indicated in several review articles (Georgi et al, ; Guérin, Fischel, Ferrero, Bozec, & Milano, ; Toren & Zoubeidi, ; Vlaeminck‐Guillem, Gillet, & Rimokh, ). Consequently, the positive feedback loop of COX‐2 upregulation triggered by iPGE 2 might also contribute to maintain a constant stimulation on these kinases involved in the progression of PC.…”

Mitogen-activated protein kinases and Hedgehog-GLI signaling in cancer: A crosstalk providing therapeutic opportunities?

“…HH and MEK1/2-ERK1/2 pathways are both involved in prostate cancer [43,44,124]. EGF signaling has been shown to increase the invasive capability of ARCaP E human prostate cancer cells via upregulation of pERK1/2 and of GLI1.…”