Journal Article

PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

Merritt P Edlind Andrew C Hsieh

2014

Overview

Prostate cancer （PCa） is the second most common malignancy among men in the world. Castration-resistant prostate cancer （CRPC） is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy （ADT）. Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor （AR） signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

• Publisher: Medknow Publications and Media Pvt. Ltd,Medknow Publications & Media Pvt. Ltd,Medknow Publications & Media Pvt Ltd,Wolters Kluwer Medknow Publications
• Subject: Androgen Antagonists - therapeutic use / androgen receptor; CRPC; kinase inhibitors; mTOR; prostate cancer; PI3K; resistance / Androgens / Clinical Trials as Topic / Development and progression / Humans / Invited Review / Kinases / Male / Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Phosphatidylinositol 3-Kinases - metabolism / Physiological aspects / Prostate cancer / Prostatic Neoplasms - etiology / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - therapy / Prostatic Neoplasms, Castration-Resistant - etiology / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - therapy / Protein biosynthesis / Proto-Oncogene Proteins c-akt - antagonists & inhibitors / Proto-Oncogene Proteins c-akt - metabolism / Receptors, Androgen - metabolism / Signal Transduction / TOR Serine-Threonine Kinases - antagonists & inhibitors / TOR Serine-Threonine Kinases - metabolism / 信号通路 / 前列腺癌 / 恶性肿瘤 / 抑制剂 / 治疗性 / 生物标记物 / 细胞增殖 / 雄激素受体