Molecular basis and therapeutic targets in prostate cancer: A comprehensive review

Abstract

Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.

Figure 1.

Androgen receptor pathway [24]. DHT: Dihydrotestosterone; T: Testosterone; AR: Androgene receptor.

Figure 2.

PI3K pathway in tumorigenesis [28, 29]. PTEN: Phosphatase and tensin homolog; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mechanistic target of rapamycin; PIP3: Phosphatidylinositol-3,4,5-triphosphate.

Figure 3.

Role of TMPRSS2-ERG gene fusion in prostate cancer [33, 34]. TMPRSS2: Transmembrane protease serine 2.

Figure 4.

Effects of NKX3.1 loss in tissue development and tumorigenesis [44]. NKX3.1: NK3 homeobox 1.

Figure 5.

Graphical abstract. AR: Androgen receptor; AR-V7: Androgen receptor splice variant 7; AMPK: 5'AMP adenosine monophosphate-activated protein kinase; ATGs: Autophagy-related genes; Bcl-2: B-cell lymphoma; CAFs: Cancer-associated fibroblasts; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; HER: Human epidermal growth factor receptor; HIFU: High intensity focused ultrasound; IGF: Insulin growth factor; MRI: Magnetic resonance imaging; NKX3-1: NK3 Homeobox 1; iPARP: Poly (ADP-ribose) polymerase inhibitors; PCA3: Prostate cancer antigen 3; PIK3-AKT-mTOR: Phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway; PTEN: Phosphatase and tensin homolog; PSA: Prostate specific antigen; TRUS: Transrectal ultrasound scan; PSMA-PET: Prostatic specific membrane antigen-positron emission tomography; TMPRSS2-ERG: Transmembrane protease serine 2 v-ets to erythroblastosis virus E26 fusion; TGF-β: Transforming growth factor beta; TMEs: Tumor microenvironment immune elements; TNF-R: Tumor necrosis factor receptor; TP53: Tumor suppressor protein 53; TRAIL: Tumor necrosis factor-ligand apoptosis-inducing ligand; TURP: Transurethral resection of the prostate.