PROTAC technology for prostate cancer treatment

Abstract

Prostate cancer (PrCa) is the most prevalent urogenital cancer in men, marked by uncontrolled cellular growth that leads to abnormal enlargement of the prostate gland. The metastatic spread of PrCa is the primary cause of mortality, causing cancer cells disseminate to distant sites, such as bones, the pelvis, and other organs. Key contributors to PrCa progression include genetic mutations, elevated androgen receptor (AR) expression, gene amplification, and the rise of AR splice variants. Although androgen deprivation therapy (ADT) remains the mainstay for early-stage PrCa treatment, its efficacy is rather temporary, as many cases advance to castration-resistant PrCa (CRPC), presenting a significant therapeutic hurdle. This review explores key biomarkers for PrCa and the latest therapeutic strategies for CRPC, with a particular focus on the innovative Proteolysis-targeting chimera (PROTAC) technology. This approach offers a novel means of degrading target proteins, and we discuss how PROTACs hold potential as effective strategies to combat resistance mechanisms in CRPC.

Figure 1.. The key biomarkers and their related signaling pathways in prostate cancer (PrCa).

Androgen stimulates androgen receptor (AR) signalling, resulting in the induction and secretion of prostate-specific antigen (PSMA), while illustrating the enzymatic function of prostate-specific membrane antigen PSMA and its role in folate metabolism and mGluR signalling pathways. AR, androgen receptor; DHT, dihydrotestosterone; HSP, heat shock protein; ARE, androgen response elements; BRD4, bromodomain-containing protein 4; PSMA, prostate-specific membrane antigen; PSA, Prostate-specific antigen; TMPRSS2-ERG, transmembrane protease serine 2:v-ets erythroblastosis virus E26 oncogene homolog; mGluR, metabotropic glutamate receptor; PI3K, Phosphoinositide 3-kinases; AKT, Protein kinase B; mTOR, mammalian target of rapamycin; PCFT, proton-coupled folate transporter; RFC1, reduced folate carrier.

Figure 2.. The current therapy landscape for PrCa.

(A). The available treatment options for different stages of PrCa. (B). Various therapies targeting BRD4, AR, PSMA, and immune check points in PrCa. ADT, Androgen Deprivation Therapy; nmCRPC, non-metastatic castration-resistant PrCa; mCRPC, metastatic castration-resistant PrCa; Lu, Lutetium; AR, androgen receptor; BRD4, bromodomain-containing protein 4; PD-L1, programmed cell death-ligand 1; PD-L2, programmed cell death-ligand 2; CTLA-4, Cytotoxic T-lymphocyte antigen 4.

Figure 3.. Targeted protein degradation therapies utilize different pathways, such as endocytosis, proteosome, and autophagy pathways.

(A). The endocytosis pathway is exploited to degrade membrane proteins (POIs) using engineered bispecific antibodies. (B). The proteosome pathway is leveraged by PROTACs to ubiquitinate and degrade target POIs. (C). AUTACs and ATTECs are designed to degrade POI or organelles in cells by hijacking the autophagy pathway. Ub, ubiquitin; ASGPR, asialoglycoprotein receptor; CXCR7, C-X-C chemokine receptor type 7; RNF43, ring finger protein 43; POI, protein of interest; KineTAC, cytokine receptor targeting chimera; LYTAC, lysosome-targeting chimera; PROTAB, proteolysis-targeting antibody; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; PROTAC, proteolysis targeting chimera; ATTEC, autophagosome-tethering compound; AUTAC, autophagy-targeting chimera; LC3, microtubule-associated protein light chain 3.

Figure 4.. The construct of PROTAC and the mechanism of controllable PROTAC.

A. The construct of PROTAC, which includes E3 ligase ligands, target protein ligands, and the linkers connecting them. The reported types of E3 ligases, linkers, and target proteins in PROTACs are summarized in the indicated boxes. B. The design and working mechanism of controllable PROTACs.

Figure 5.. The potential molecular mechanisms underlying CRPC.

The scheme illustrates seven potential mechanisms of CRPC, including aberrant activation of AR, AR amplification, intra-tumoral steroid synthesis, AR splicing variants, AR promiscuity, post-translational modifications of AR, and coregulator modification.