Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

Abstract

Prostate cancer (PCa) affects millions of men globally. Due to advances in understanding genomic landscapes and biological functions, the treatment of PCa continues to improve. Recently, various new classes of agents, which include next-generation androgen receptor (AR) signaling inhibitors (abiraterone, enzalutamide, apalutamide, and darolutamide), bone-targeting agents (radium-223 chloride, zoledronic acid), and poly(ADP-ribose) polymerase (PARP) inhibitors (olaparib, rucaparib, and talazoparib) have been developed to treat PCa. Agents targeting other signaling pathways, including cyclin-dependent kinase (CDK)4/6, Ak strain transforming (AKT), wingless-type protein (WNT), and epigenetic marks, have successively entered clinical trials. Furthermore, prostate-specific membrane antigen (PSMA) targeting agents such as ¹⁷⁷Lu-PSMA-617 are promising theranostics that could improve both diagnostic accuracy and therapeutic efficacy. Advanced clinical studies with immune checkpoint inhibitors (ICIs) have shown limited benefits in PCa, whereas subgroups of PCa with mismatch repair (MMR) or CDK12 inactivation may benefit from ICIs treatment. In this review, we summarized the targeted agents of PCa in clinical trials and their underlying mechanisms, and further discussed their limitations and future directions.

Fig. 1

Overview of genetic alterations and therapeutic strategies in PCa. a Genetic alterations in localized PCa, metastatic castration-sensitive PCa, and metastatic castration-resistant PCa.^– b Common somatic mutations at different disease stages of PCa. c Overview of therapeutic targeting strategies for the treatment of PCa

Fig. 2

AR signaling pathway and targeted therapeutic approaches in PCa. Androgen synthesis is regulated by the hypothalamic–pituitary–gonadal axis. When androgens such as testosterone (T) and DHT bind to AR, AR releases itself from the heat shock protein complex, translocates into the nucleus, and promotes gene transcription to accelerate tumor progression. Targeting the androgen-signaling axis includes multiple approaches, such as targeting GnRH to prevent luteinizing hormone release, targeting CYP17A1 to restrain androgen synthesis, or directly targeting AR to inhibit AR transcription activity. Parts of images generated from BioRender (https://biorender.com/)

Fig. 3

The vicious cycle of bone metastasis and targeting strategies in PCa. Tumor cells in bone secrete osteolytic cytokines such as RANKL, PTHrP, GM-CSF, MMPs, IL-6, IGFs, FGFs, endothelin 1, GDF15, DKK-1, and WNTs to induce osteoclast-mediated bone resorption, while osteoclasts release bone-stored factors such as TGFβ, IGFs, and Ca²⁺ that stimulate tumor cell proliferation, establishing a vicious cycle. Targeting the bone microenvironment (such as bone-targeted radioisotopes, bisphosphonates, and RANKL inhibitors) is effective to manage bone metastases in PCa

Fig. 4

Inhibition of PARP mediates synthetic lethality in PCa. When PARP1/2 are pharmacologically inhibited, the accumulation of SSBs by PARP inhibition can progress to DSBs, which are usually repaired through HR. The DSBs can be fixed if the DNA repair system is intact in cells; however, PARP inhibition can lead to lethality if a cell is lacking HR repair capacity (mutations of BRCA1, BRCA2, or ATM). BCL2 overexpression, TMPRSS2-ERG fusion, SPOP mutation, PTEN loss, and CHD1 deletion are also linked with an impaired DNA damage response phenotype, which might increase the therapeutic effectiveness of PARP inhibition

Fig. 5

Mechanisms of elicitation of T-cell-mediated cancer killing in MMR- or CDK12-deficient cancer cells. A dysfunctional MMR system or CDK12 generate neoantigens through mutant peptides, or frameshift mutations and indels in coding microsatellites. These neoantigens are presented to the cell surface by MHCI molecules, thus facilitating T-cell-mediated tumor cell killing, which can be enhanced by ICIs, such as CTLA4 inhibitors, PD1 inhibitors, and PD-L1 inhibitors

Fig. 6

Schematic of major histone or DNA modification and the key modifiers implicated in PCa. Aberrant histone (such as acetylation, methylation, phosphorylation, and ubiquitination) or DNA modifications (such as methylation) might upregulate oncogenes or reduce tumor suppression genes; thus, targeting these epigenetic modifications is an attractive strategy to treat PCa. Several compounds (such as EZH2 inhibitors, LSD1 inhibitor, BET inhibitors, HDAC inhibitors and DNMT inhibitors) based on epigenetic targets have entered clinical trials in succession

Fig. 7

The WNT signaling pathway and targeting therapeutic strategies. WNT ligands bind to FZD and LRP5/6 receptors to phosphorylate DVL, and then phosphorylated DVL recruits the destruction complex to the plasma membrane. This inhibits GSK3 and prevents phosphorylation of β-catenin, resulting in the stabilization and accumulation of β-catenin proteins to form a complex with TCF/LEF in the nucleus, thereby activating the transcription of downstream target genes. There are several targeting strategies that prevent the activation of WNT signaling, such as targeting WNT ligands and their receptors, inhibiting the WNT secretion by targeting porcupine, and disrupting the interaction between CBP and β-catenin