Castration-Resistant Prostate Cancer: From Uncovered Resistance Mechanisms to Current Treatments

Abstract

Prostate cancer (PC) is the second most common cancer in men worldwide. Despite recent advances in diagnosis and treatment, castration-resistant prostate cancer (CRPC) remains a significant medical challenge. Prostate cancer cells can develop mechanisms to resist androgen deprivation therapy, such as AR overexpression, AR mutations, alterations in AR coregulators, increased steroidogenic signaling pathways, outlaw pathways, and bypass pathways. Various treatment options for CRPC exist, including androgen deprivation therapy, chemotherapy, immunotherapy, localized or systemic therapeutic radiation, and PARP inhibitors. However, more research is needed to combat CRPC effectively. Further investigation into the underlying mechanisms of the disease and the development of new therapeutic strategies will be crucial in improving patient outcomes. The present work summarizes the current knowledge regarding the underlying mechanisms that promote CRPC, including both AR-dependent and independent pathways. Additionally, we provide an overview of the currently approved therapeutic options for CRPC, with special emphasis on chemotherapy, radiation therapy, immunotherapy, PARP inhibitors, and potential combination strategies.

Keywords: PARP inhibitors; androgen deprivation therapy (ADT); androgen signaling; castration-resistant prostate cancer; chemotherapy; immunotherapy; radionuclide therapy.

Figure 1

Mechanisms of castration-resistant prostate cancer (CRPC). AR overexpression enables the survival and proliferation of tumor cells in limited-androgen conditions during androgen suppression treatment. A high AR expression level can be due to AR gene amplification, epigenetics, and miRNA modulation (1). Point mutations in the ligand-binding domain of the AR gene lead to the increased affinity of the mutated AR (mAR) to other hormones, such as progesterone and estrogen, thereby modulating androgen-responsive gene transcription independently from androgen (2). The emergence of AR-splicing isoforms, such as AR3 (also called AR-V7), AR4, and AR5, encoding the truncated AR protein (tAR), which lacks the ligand-binding domain, results in constitutive activation of the AR, thereby promoting variant-carrying tumor cells to ignore the need for androgen (3). Overexpression of AR coactivators and the decreased expression of AR corepressors will result in an increase in AR-regulated transcription (4). Increased production of 5α-reductase can provide sufficient androgens for AR activation in cancer cells (5). CRPC can be induced by outlaw pathways in which AR signaling can be activated in a ligand-independent manner by other molecules than androgens, such as growth factors, cytokines, and kinases (6). The bypass pathways, involved in CRPC progression, increase the activity of MAPK, PI3K, and PCK cascades, leading to either the stimulation of alternative growth pathways or the enhancement of survival signaling independently from AR signaling. Alternative pathways also involve the overexpression of heat-shock protein 27 (HSP27), which mediates its cytoprotective function by protecting its interacting proteins (eIF4E, TCTP, Menin, DDX5) from their degradation by the proteasome (7) (↑ in red: increase, ↓in red: decrease).

Figure 2

Current therapies for castration-resistant prostate cancer (CRPC) treatment. Along with androgen deprivation therapy (ADT), the approved therapies by the FDA and EMA to treat CRPC include chemotherapy (A), immunotherapy (B), radiotherapy (C), and PARP inhibitors (D). (A) Chemotherapy: (1) Docetaxel and cabazitaxel prevent microtube depolymerization, therefore inhibiting cell division and causing cell death. Mitoxantrone could induce cell death via the inhibition of topoisomerase II (2) and DNA damage induction (3). (B) Immunotherapy: Sipuleucel-T stimulates the T-cell anti-tumor activity by targeting the prostatic acid phosphatase (PAP) protein—an overexpressed protein in prostate cancer cells. (1) Antigen-presenting cells (APCs) isolated from patients will digest PAP proteins into small peptides and display these PAP peptides on their surfaces. (2) APCs present PAP peptides to T-cells, which can then recognize cancer cells that express PAP on their surfaces and activate immune cytotoxic effects to kill CRPC cells (3). Immune checkpoint inhibitors, including pembrolizumab and dostarlimab, are utilized to combat cancer cells by blocking immune checkpoint pathways, which reactivates cytotoxic lymphocytes antitumor responses. These medications work by preventing interaction between the PD-1 receptor and its ligands (PD-L1 and PD-L2), consequently inhibiting the programmed death 1 pathway and triggering the immune response against cancer cells. (C) Targeted Radiation Therapy: (1) Radium-223 induces cell death by generating DNA damage via emitting high-energy α-particles; (2) [¹⁷⁷Lutetium]-PSMA-617 contains the ligand of the prostate-specific membrane antigen of prostate cancer cells (PSMA-617) conjugated with radiolabeled ¹⁷⁷Lutetium. This drug causes DNA damage via the release of Ɓ and γ particles, thus leading to cell death. (D) PARP Inhibitors: The inhibition of PARP enzymes leads to double-strand DNA breaks from single-strand DNA breaks (SSBs). (1) The BRCA1/2 gene will be activated to repair DSBs and promote cell survival. (2) Cells with BRCA1/2 alterations cannot repair DSBs, leading to DNA damage and inducing cell death.