Molecular pathogenesis and progression of prostate cancer

Abstract

Prostate cancer (PCa) is the most commonly diagnosed noncutaneous malignancy and second leading cause of cancer-related deaths in US males. Clinically, locally confined disease is treated surgically and/or with radiation therapy. Invasive disease, however, must be treated with pharmacological inhibitors of androgen receptor (AR) activity, since disease progression is fundamentally reliant on AR activation. However, despite initially effective treatment options, recurrent castration-resistant PCa (CRPC) often occurs due to aberrant reactivation of AR. Additionally, it is appreciated that many other signaling molecules, such as transcription factors, oncogenes, and tumor suppressors, are often perturbed and significantly contribute to PCa initiation and progression to incurable disease. Understanding the interplay between AR signaling and other signaling networks altered in PCa will advance therapeutic approaches. Overall, comprehension of the molecular composition promoting neoplastic growth and formation of CRPC is paramount for developing durable treatment options.

Figure 1. Molecules implicated in PCa initiation and progression

Initiation of PCa and progression to CRPC involves deregulation of numerous signaling pathways. Expression of NKX3.1, FOXA1, and Myc is altered in early stage PCa, which plays a role in disease initiation. However, there are currently no effective means to target these aberrations. Additional molecules are perturbed in transition to CRPC and are capable of being pharmacologically inhibited. TMPRSS2:ERG fusion expression promotes invasive phenotypes and can be inhibited by PARP1 inhibitors, RB status (loss of expression or function) can stratify patients for responsiveness to chemotherapy or CDK inhibitors, and loss of PTEN expression increases PI3K/AKT/mTOR signaling, which can be inhibited with targeted inhibitors. AR signaling is central to PCa and progression to CRPC. Prior to CRPC, invasive PCa is treated with AR antagonist bicalutamide, although novel inhibitors MDV3100, ARN-509, and EPI-001 are in clinical trials and may provide more effective treatment options. In response to antagonists, AR activity is regained through increased expression, gain-of-function mutations, constitutively active splice variants, posttranslational modifications (PTMs), and intratumoral androgen synthesis. Abiraterone inhibits autocrine androgen synthesis and is approved for CRPC treatment. Red and green arrows indicate decreased or increased protein expression/activity detected in PCa, respectively.