Molecular Drivers of Prostate Cancer Metastasis: Emerging Targets for Precision Therapy

Abstract

Prostate cancer (PCa) stands as one of the primary cancer diseases affecting male health and represents the principal reason behind death when metastasis develops during late-stage disease. The spread of prostate cancer from its initial site demands intricate molecular interactions through signaling pathways which permit cancer cells to break their attachment to the original tumor mass and form secondary tumor sites in distant organs. Prostate cancer metastasis depends heavily on three main molecular pathways which include the PI3K/AKT signaling cascade along with Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT) signaling mechanisms. The deregulation of these signaling pathways creates strong contributions toward prostate cancer spread during metastasis and reduction of response to standard treatment methods. Presently available androgen deprivation therapy and chemotherapy have proven successful to some extent yet insufficient for effective treatment of both castration-resistant prostate cancer (CRPC) and metastatic disease. The development of therapies which block AKT signaling combined with Wnt signaling inhibition and reversal of EMT processes creates new treatment opportunities for better cancer outcome results. The combined use of immunotherapy with personalized medicine along with liquid biopsy technologies will improve therapeutic effects by enabling real-time tracking of disease evolution and treatment response. This analysis investigates the molecular processes that drive prostate cancer metastasis and the present therapeutic solutions and the upcoming therapies that try to block these pathways. Numerous treatment approaches and precision medicine strategies combining the integrated treatment approaches may lead to improved therapeutic benefit with fewer adverse effects while delivering more personalized and effective care. This review will majorly focus on the molecular pathways and preclinical treatment options that support metastatic prostate cancer, but briefly outline the clinical progress that is currently shaping the precision therapeutic models.

Keywords

prostate cancer metastasis PI3K/AKT signaling pathway Wnt/β-catenin pathway epithelial-mesenchymal transition (EMT)precision oncology

Introduction

Worldwide men suffer from prostate cancer which ranks as the primary malignancy affecting them and metastatic prostate cancer leads to the most cancer-related male deaths. Older male adults represent the main group who develops this disease since most prostate cancer diagnoses occur after age 65. The management of prostate cancer faces considerable difficulties from metastasis because metastatic tumors typically demonstrate decreased responsiveness to established therapy methods. The biological process of prostate cancer metastasis manifests through cancer cell detachment from their origin along with invasion beyond tissue borders until reaching ultimate metastases in bones and lungs and liver.¹ According to the latest national estimates based on the Global Burden of Disease Study, the trends of incidence and mortality of prostate cancer have been showing consistent rise in China. Xue et al² stated that the age-specific incidence and mortality rates have increased since 1990, and heterogeneity is acutely experienced regionally, and the trend is increasing, especially among the elderly male population. Such discoveries highlight the increasing community health importance of prostate cancer in Asia and the urgency of global exercise to prevent and control such cancer in a manner that is molecularly directed.

Knowledge regarding prostate cancer metastasis mechanisms at the molecular level helps advance better therapeutic approaches. The mutation of specific genes drives tumor cells to stay alive within different tissues while outsmarting immune responses and adapting to new nearby environments during metastasis. The development of prostate cancer metastasis depends primarily on epithelial-mesenchymal transition (EMT) as well as PI3K/AKT signaling, Wnt/β-catenin signaling and Transforming Growth Factor Beta (TGF-β) signaling. During EMT epithelial cells convert into mesenchymal cells which gain superior abilities to invade surrounding tissues through coordinated cellular changes. Abnormal pathway activities generate conditions which enable tumor cells to move and invade other tissues in the metastatic process.^3,4

Among all altered signaling pathways prostate cancer exhibits the PI3K/AKT pathway occurs with the highest frequency. Cell survival together with growth and metabolic functions operate under the significant regulation of this pathway. This pathway shows evidence of triggering primary tumor development and metastasis formation and shows involvement in the creation of resistance to the therapy known as androgen deprivation therapy (ADT). The AKT1 gene serves as a critical factor for prostate cancer metastasis because it contains the genetic code for an important element in the PI3K/AKT signaling pathway. The AKT1 gene shows frequent polymorphisms which appear in metastatic prostate cancer cases as well as they link to tumor cell aggressiveness and reduced treatment effectiveness.^5,6

Metastasis of prostate cancer depends on Wnt/β-catenin signaling as an essential signaling pathway that controls cell proliferation alongside differentiation and migration patterns. Prostate cancer cells demonstrate frequent upregulation of this pathway while metastatic tumors heavily depend on it for their development. Activating Wnt signaling at abnormal levels allows cancer cells to migrate and invade tissues which enables their movement toward different organs where prostate cancer spreads. Studies have demonstrated how Wnt signaling interacts with cancer stem cells (CSCs) because these cells play a part in prostate cancer metastasis and therapeutic resistance.^7,8

Prostate cancer metastasis receives regulation from Two signaling pathways together with TGF-β pathway. The cell-based protein TGF-β manages various processes related to cell proliferation as well as differentiation and apoptosis functions. During cancer development TGF-β promotes metastasis by creating EMT conditions that result in the transition of tumor cells into a mesenchymal state which significantly boosts their capacity to migrate towards distant tissues. Scientific research shows that improper TGF-β signaling facilitates prostate cancer metastasis to the bones which represents a dominant metastatic site.⁹

The medical field now dedicates greater attention to create drug treatments that block molecular pathways. Metastatic prostate cancer remains a major challenge for current treatments composed of ADT combined with chemotherapy and immunotherapy because they both result in treatment failure through resistance development and cause major adverse effects. The PI3K/AKT pathway along with Wnt/β-catenin signaling and EMT represent new therapeutic targets because preclinical research together with clinical trial results demonstrate initial promising data. The targeted therapeutic strategies aim to target particular molecular factors of metastasis which prevents prostate cancer spread and enhances patient treatment results.^9,10

Scientists have developed a better grasp of prostate cancer metastasis pathways which resulted in discovering new therapeutic targets. Direct or indirect engagement of these pathways creates new opportunities to find better treatment strategies against metastatic prostate cancer. Current research persists in developing effective therapeutic approaches that combine metastatic cell targeting methods with resistance management strategies which arise during treatment. Ongoing research into prostate cancer metastasis molecular biology serves as a necessity to build better therapeutic strategies that match individual patients’ needs.

New transcriptomics systems have made the molecular classification of prostate cancer refined and are currently used to inform the risk assessment and targeted treatment. The 14-Pathway Classification of Prostate Cancer (PCS) and the PAM50 intrinsic classification splits tumors into biologically different groups that differ in aggressiveness, androgen -signalling activity, and metastatic tropism. Bone-metastatic-specific-analyses also indicate the enrichment of osteomimicry and stem-like-phenotype related pathways. Taken together, these types of classifications bolster individualized prognostication and precision-therapy design.¹¹ Despite significant changes in clinical practice with major late-phase trials, this narrative review centers on the systems of molten and early-phase therapeutic basis of prostate-cancer metastasis and incorporates major clinical discoveries simply to present them in the context of the translated work.

A systematic narrative approach was used in order to be able to cover current evidence evenly. Literature search was performed through PubMed, Scopus and Google scholar in the period between January, 2000 and January, 2025 and has used the following key words together; prostate cancer metastasis, PI3K AKT signaling, Wnt -catenin signaling, epithelial-mesenchymal transition, androgen receptor signaling, cancer stem cells, radioligand therapy, Poly (ADP)-ribose) polymerase (PARP) inhibitors, and precision oncology. Peer-reviewed articles were given the first priority, including mechanistic research, preclinical research, first clinical trials, and phase 3 research which gave translational relevance. Articles were included where they dealt with molecular mediators of metastasis or focused therapeutic interventions. Reports, commentaries, or other studies other than involving molecular pathways were excluded. Appraisal of evidence was done in the form of narration based on the scientific rigor, relevance and conformity to the current clinical knowledge. This combination helped to combine the mechanistic knowledge with new therapeutic information without losing the narrative review format.

A flow diagram is not applicable to this review article, as it is not a systematic review.

Molecular Mechanisms of Metastasis

Prostate cancer spreads throughout the body and poses persistent problems in clinical oncology practice because it represents one of the central factors contributing to male death due to cancer. Prostate cancer cell dissemination throughout the body results in most patient deaths and causes their terminal illnesses. Prostate cancer metastasis occurs through an established sequence which begins with local tissue penetration followed by blood or lymphatic system entry and subsequent exit into target organs and concludes with new colony formation. Research on molecular metastatic mechanisms requires completion because it provides essential directions for creating new therapeutic approaches targeting metastatic progression.

The metastasis of cancer requires multiple signaling systems through EMT as well as the PI3K/AKT pathway and Wnt/β-catenin signaling androgen receptor (AR) signaling together with cancer stem cell (CSC) dynamics. These biological pathways lead to the control of cell survival along with migration and invasion and resistance toward current treatment methods thus presenting essential targets for developing new therapies.

Epithelial-Mesenchymal Transition (EMT)

The development of prostate cancer metastaic properties relies heavily on EMT. EMT represents a cellular process through which epithelial cells switch their properties to generate mesenchymal cells that demonstrate heightened mobility including invasiveness. Carcinoma cells progress through this transition because it enables their detachment from the primary tumor which allows them to spread into neighboring tissues and other organs. Cellular transformation via EMT leads to complete modifications in cell appearance as well as cytoskeleton construction and cell bonding element regulation. The process of E-cadherin regulatory changes during EMT leads to decreased epithelial cell adhesion whereas the simultaneous upregulation of mesenchymal markers N-cadherin, vimentin, and fibronectin occurs.^12,13

The TGF-β pathway and Wnt/β-catenin signaling and PI3K/AKT pathway jointly initiate EMT in prostate cancer cells. Snail functions as one of the best-examined transcription factors for EMT regulation in prostate cancer by suppressing E-cadherin gene expression and elevated expression of mesenchymal factors. The transcription factors Twist together with Slug and ZEB1/2 significantly contribute to EMT regulation and increase prostate cancer cell invasiveness.¹⁴

The capability of prostate cancer cells to perform EMT improves their migration and invasive properties alongside establishing resistance to chemotherapy and radiation therapy based on research findings. Mesenchymal-like cancer cells resist apoptosis because they survive poorly suitable conditions of the bloodstream and distant organs. Treatment outcomes can improve when medical teams target molecular pathways which regulate EMT for metastasis reduction.¹⁵

The molecular markers essential for EMT in prostate cancer appear in Table 1 as they function as vital factors for metastasis. The table shows that during EMT cancer cells lose the epithelial cell adhesion molecule E-cadherin which allows them to detach from the primary tumor. The transformation leads to elevated levels of both vimentin and N-cadherin which promotes cellular movement and inturn drives invasion. EMT is regulated by Snail which serves to suppress E-cadherin expression as well as activate the mesenchymal characteristics along with Twist. These markers act together to enhance prostate cancer invasiveness while enabling cell metastasis to distant organs.^15–17

Table 1.

Key Molecular Markers of EMT in Prostate Cancer.

Marker	Role in EMT	References
E-cadherin	Downregulated during EMT	¹⁶
Vimentin	Upregulated during EMT	¹⁸
N-cadherin	Upregulated during EMT	¹⁹
Snail	Transcription factor promoting EMT	²⁰
Twist	Transcription factor promoting EMT	¹⁷

The image in Figure 1 presents EMT occurrence in prostate cancer. The scientific illustration shows how epithelial cells transform into mesenchymal cells through a cellular process that increases their motility and invasion potential by enhancing N-cadherin and vimentin expression along with diminishing the expression of E-cadherin. The mesenchymal phenotype develops through the action of Snail, Twist and Slug transcription factors that simultaneously suppress E-cadherin expression.^17,20 The figure demonstrates cell type characteristics while detailing molecular elements during EMT while showing how these changes create cells that become more mobile and less susceptible to cell death thus enabling cancer metastasis.²¹

Figure 1.

Epithelial-Mesenchymal Transition (EMT) in Prostate Cancer Metastasis.

PI3K/AKT Signaling Pathway

Prostate cancer metastasis regulation heavily depends on the crucial PI3K/AKT signaling pathway as one of its principal signaling networks. The phosphoinositide 3-kinase (PI3K) becomes activated by growth factors to make phosphatidylinositol 3,4,5-trisphosphate (PIP3) by transforming phosphatidylinositol 4,5-bisphosphate (PIP2) then triggers AKT recruitment to the plasma membrane for subsequent phosphorylation-based activation. When activated AKT proceeds to phosphorylate multiple targets which control survival functions and metabolic regulation and capabilities of cell growth. The PI3K/AKT signaling pathway shows frequent abnormal activation rates within prostate cancer tumors particularly in cases of metastasis and castration-resistant prostate cancer (CRPC). Moderate activation of AKT protects malignant cells from death through Bcl-2-associated death promoter (BAD) regulation and starts cell cycle events through mammalian target of rapamycin (mTOR) activation.²²

The metastasis-associated functions of EMT as well as cell migration and invasion receive regulation through the PI3K/AKT pathway. The invasive character of prostate cancer cells advances through AKT pathway activation which makes transcription factors including Snail and Slug more active.²³ The protein AKT plays an important role in EMT while activating the expression of matrix metalloproteinases (MMPs) that degrade extracellular matrix (ECM) to enable cancer cell penetration into surrounding tissues.²⁴

Poor clinical outcomes together with treatment resistance frequently appear when Prostate cancer develops PI3K/AKT pathway abnormalities. Metastatic prostate cancer frequently manifests loss or mutation of PTEN which results in constitutive AKT pathway activation given that PTEN functions normally to control the PI3K/AKT pathway. Advanced prostate cancer often shows frequent genetic abnormalities of the PIK3CA gene that carries instructions for the catalytic subunit of PI3K. Researchers at present investigate PI3K/AKT inhibitors to treat metastatic prostate cancer.²⁵

The PI3K/AKT signaling pathway serves as an essential mechanism for prostate cancer metastasis and researchers depict it in Figure 2. Upon binding of insulin-like growth factor (IGF) and epidermal growth factor (EGF) to receptor tyrosine kinases (RTKs) the PI3K pathway gets activated.²⁶ The enzyme activity of activated PI3K converts PIP2 to PIP3 while it positioning protein kinase B (AKT) at the plasma membrane.²⁷ Activated AKT stimulates mTOR for cellular growth stimulation as well as BAD inhibition to promote survival while the Glycogen synthase kinase-3 beta (GSK3β) controls cell cycle advancement and transcription factors such as Snail and Twist initiate EMT.²⁸ The molecular actions of the PI3K/AKT signaling pathway boost prostate cancer cells to grow and spread while ensuring survival thus creating it as a viable therapeutic target.²⁶

Figure 2.

PI3K/AKT Signaling in Prostate Cancer Metastasis.

Wnt/β-Catenin Signaling Pathway

Through its regulatory role the Wnt/β-catenin signaling pathway controls three essential cellular functions which include cell proliferation and cell differentiation together with cell migration. Anti-Wnt/β-catenin signaling pathway activation plays a role in the disease recruitment of prostate cancer through all tumor stages including tumorigenesis and metastatic formation. The β-catenin protein undergoes normal regulatory pathways through which cytoplasmic breakdown occurs. β-Catenin degradation prevention occurs in cancer cells due to Wnt pathway component mutations which results in protein buildup within the cell and subsequent nuclear transfer and target gene transcription promoting cell proliferation and invasion.^29,30

The Wnt/β-catenin signaling pathway functions importantly to govern CSCs in prostate cancer because these CSCs serve as initiators of disease onset and progression as well as metastatic relapses. Research shows that CSCs possess two key features - self-renewal and resistance to standard treatments while β-catenin controls CSC survival genes that promote metastasis.³¹ The metastatic potential of prostate cancer cells develops via the blended interaction between β-catenin signaling and PI3K/AKT signaling and EMT pathways.

Active medical research focuses on developing therapeutic methods to target the Wnt/β-catenin pathway. The science of developing inhibitors for Wnt signaling pathway components with β-catenin and upstream receptors represents current research for treating late-stage prostate cancer. Currently science faces obstacles to develop inhibiting compounds for this pathway because they struggle to hit their target specifically and stay away from additional unwanted effects.³²

Figure 3 illustrates the Wnt/β-catenin signaling pathway during prostate cancer metastasis which starts when Wnt ligands connect to Frizzled receptors on cells next to the membrane leading to normal DVL protein activation.²⁹ DVL stops the activity of GSK3β enzyme from breaking down the β-catenin protein resulting in its buildup within the cell cytoplasm.³³ Nuclear translocation of stabilized β-catenin allows the protein to interact with transcription factors which leads to EMT-related and CSC-related gene activation.²⁹ Prostate cancer cells change their transcription patterns through these alterations which strengthens their ability to migrate and invade leading to tumor metastasis and treatment resistance. Prostate cancer aggressiveness results from the dual influence of Wnt signaling combined with PI3K/AKT pathways which makes β-catenin a leading factor for malignant prostate phenotype development. The Wnt/β-catenin axis components are now examined as an encouraging therapeutic method for treating metastatic prostate cancer.³⁴

Figure 3.

Wnt/β-Catenin Signaling in Prostate Cancer Metastasis.

Androgen Receptor (AR) Signaling

Prostate cancer development alongside progression depends heavily on the AR as its main regulatory factor. Advanced prostate cancer receives its main therapeutic intervention from ADT which blocks and reduces androgen activity in the body. After undergoing castration therapy most prostate cancer patients develop castration-resistant prostate cancer that maintains its growth pattern when lowered androgen levels become present. Multiple biological processes such as AR gene amplification with mutations along with constitutively active AR splice variant expression keep AR signaling active in prostate cancer cells.³⁵

The expression of tumor growth and metastatic genes and drug-resistance genes in prostate cancer cells falls under the regulation of AR signaling pathways. Recent medical research demonstrates that AR controls the expression of three EMT-related genes named Snail, Twist and Slug whose presence drives prostate cancer cell metastasis.³⁶ AR signaling forms a complex network of interactions with PI3K/AKT pathway along with Wnt/β-catenin signaling to foster prostate cancer metastasis according to research.⁵

Laboratory research on advanced anti-androgen compounds as well as receptor antagonists has produced frontiers in CRPC resistance treatment. These medications named enzalutamide and apalutamide exhibit clinical effectiveness for preventing CRPC disease progression and metastatic spread.³⁷

Figure 4 depicts the biological pathway that involves the AR signaling mechanism within prostate cancer cells after androgens tie to AR present in cytoplasmic fluid. The androgen receptor complex enters the nucleus to activate the transcription of genes that include EMT-associated factors including Snail, Twist, and Slug. Through its attachment to other metastatic-promoting signaling pathways that include PI3K/AKT and Wnt/β-catenin the AR signaling develops extensive communication networks which sustain tumor growth and spreading between organs. The figure features therapeutic drug administration through ADT programs notably including the next-generation anti-androgen medications for delaying tumor progression in CRPC.³⁸

Figure 4.

AR Signaling in Prostate Cancer Metastasis.

Cancer Stem Cells (CSCs) and Metastasis

A minority of tumor cells which behave as CSCs display the capacity to both reproduce themselves indefinitely and develop into multiple cell varieties. Medical experts believe that these cancer cells start and advance metastatic spread in prostate cancer tumors. The resistance of CSCs against conventional medical treatments creates these cells as crucial therapeutic targets because they remain unresponsive to chemotherapy and radiation therapy. A group of signaling pathways including Wnt/β-catenin, Notch, PI3K/AKT and TGF-β act as regulators for prostate CSCs. The survival and self-renewal mechanism of CSCs is enabled by these pathways as such capabilities drive prostate cancer cell metastasis. β-Catenin signaling represents a main signaling mechanism which sustains CSC characteristics and drives metastasis according to recent studies.^39,40 By targeting CSC pathways medical science has demonstrated the potential to minimize prostate cancer metastasis so patients achieve better treatment results.

CSCs initiate prostate cancer metastasis from their original tumor positions through their self-renewing capacity combined with resistance to traditional treatment modalities as Figure 5 depicts. The invasion of these CSCs into neighboring tissues leads to bloodstream entry where “Invasion” and “Circulation” occur thus enabling their transit to distant organs particularly bone. Cancer stem cells activate new tumor formation when they reach a secondary location thus enhancing the metastatic process. Through the diagram researchers display four signal pathways which manage CSC actions alongside driving their spreading features while protecting against treatment success.

Figure 5.

Role of Cancer Stem Cells (CSCs) in Prostate Cancer Metastasis.

Current and Emerging Therapeutic Targets

Treatments for prostate cancer metastasis face important obstacles since they work efficiently in limited cases of early disease stage progression. When prostate cancer spreads to different parts of the body especially bones and lymph nodes standard treatment methods become inadequate. Knowledge about prostate cancer metastasis molecular foundation has led to the development of targeted medicines intended to disrupt the progression mechanisms of metastasis. New treatment approaches focus on PI3K/AKT pathway inhibition along with Wnt/β-catenin signaling control and both EMT blockade and AR signaling suppression. Targeted therapies and immunotherapies developed over time now provide critical new options in treating patients who have metastatic prostate cancer.

PI3K/AKT Pathway Inhibition

Tumor cell survival and proliferative and invasive functions of prostate cancer stem from the PI3K/AKT signaling pathway activation which promotes cancer progression. The PIK3CA gene frequently mutates together with PTEN loss which scientists find frequently appears in advanced and metastatic prostate cancer.⁵ The therapeutic repression of the PI3K/AKT pathway emerges as a principal treatment approach for combating metastatic prostate cancer.

Current Therapies

The PI3K/AKT pathway holds limited advancement in its therapeutic development. Among these early-stage approaches mTOR inhibitors everolimus and temsirolimus maintain the status as the predominant drug class. These drugs stop the mTOR activity which manages both cell growth and proliferation.⁴¹ Complex signaling within the tumor microenvironment has limited the effectiveness of these agents.

Emerging Therapies

Scientists developed more specific inhibitors targeting the enzymes PI3K and AKT during the previous several years. Clinical trials demonstrate that ipatasertib and similar AKT inhibitors bring promising treatment response to metastatic prostate cancer patients treated with androgen receptor signaling inhibitors.⁴² The combined treatment uses multiple substances that target cancer cell resistances which can develop when using single-active therapy alone.

The effectiveness of suppressing metastatic prostate cancer cell growth with PI3K inhibitors is currently evaluated by researchers using the drug buparlisib in clinical trials. These inhibitor molecules stop the PI3K pathway at its initial stages to prevent activation of AKT and downstream survival pathways.⁴³ Although many of these inhibitors have been advanced to first-phase clinical trials, long-term therapeutic responses have been short, and resistance has often been overcome by parallel pathway compensatory activation.

The PI3K/AKT signaling pathway works through prostate cancer metastasis as Figure 6 demonstrates all essential molecules involved. Growth factors activate RTKs and then trigger the process which leads to PI3K activation. PI3K uses PIP2 as a substrate for conversion into PIP3 thus triggering AKT recruitment and subsequent activation steps. AKT achieves survival and growth promotion through its downstream targets which comprise the protein synthesizing mTOR and the apoptosis blocking BAD. AKT enzyme activation subsequently causes GSK3β activation and transcription factors Snail and Twist become activated which leads to cell EMT and tumor metastasis. Through its inhibitory action on PI3K activity PTEN decreases the levels of activated AKT. Therapists use AKT inhibitors together with PI3K inhibitors alongside other treatments to stop the advancement of cancer metastasis.^44,45 This figure demonstrates the fundamental molecular relationships while presenting their relevance to prostate cancer treatment methods.

Figure 6.

Targeting the PI3K/AKT Pathway in Prostate Cancer Metastasis.

Wnt/β-Catenin Signaling Inhibition

Another important signaling pathway which regulates prostate cancer metastasis is known as Wnt/β-catenin. Pathway abnormalities result in increased stability of β-catenin protein that enters the nucleus where it activates genes required for tumorous growth and metastasis. The β-catenin signaling pathway leads to Prostate cancer cell EMT which gives cells their invasive capabilities according to research findings.²⁹

Current Therapies

FDA has not authorized medical treatments that directly target the Wnt/β-catenin signaling pathway in prostate cancer cases. In preclinical models researchers have discovered two Wnt signaling inhibitor substances known as LGK974 and IWP-2 which show promise as therapeutic agents. The action of Wnt signaling inhibitors leads to receptor-ligand barrier disruption which prevents β-catenin activation and stops its movement into the nucleus.⁴⁶ The Wnt/β-catenin pathway inhibitors demonstrate promising results in preclinical examinations yet they have not succeeded in clinical trials for prostate cancer treatment. It is important to note that all the Wnt pathway inhibitors mentioned have shown no clinically relevant activity in prostate cancer and all the available data are pre-clinical thus limiting their direct therapeutic use.

Emerging Therapies

Scientists now explore destruction complex targeting as a way to suppress β-catenin destruction which normally happens when Wnt signaling is absent. XAV939 serves as a Tankyrase inhibitor which makes destruction complex stable so β-catenin degradation occurs with consequent Wnt signaling suppression.⁴⁷ Medical researchers are evaluating these inhibitors in clinical trials for their therapeutic applications in metastatic prostate cancer. In spite of promising in-vitro results, clinical translation of Wnt pathway inhibitors is still limited by the aspect of specificity, off-target toxicity to normal tissues, and the critical nature of Wnt signaling in normal stem cells homeostasis.

Small interfering RNA (siRNA) technology united with CRISPR-based gene editing approaches show promise in directly silencing β-catenin alongside key Wnt signaling pathway components. Particularly specific and tailored treatments from these scientific approaches provide the potential to stop metastatic progression at its genetic origins.

Table 2 lists Wnt/β-catenin signaling inhibitor research for prostate cancer that shows their active mechanisms with current development stages and relevant citation information. The preclinical inhibitor LGK974 functions by blocking release of Wnt ligands to avoid activating the Wnt/β-catenin pathway.^48,49 IWP-2 inhibits Wnt receptor binding to suppress β-catenin stabilization and exists in the same developmental stage as preclinical drugs.⁴⁹ The Tankyrase inhibiting molecule XAV939 stabilizes the β-catenin degradation complex thereby resulting in β-catenin degradation since it is also currently in preclinical development.⁵⁰ The direct β-catenin expression inhibition by siRNA has entered clinical trials because scientists believe it could lead to therapeutic solutions.⁵¹ Multiple therapeutic strategies based on Wnt/β-catenin signaling pathway blockage represent potential treatment options for avoiding prostate cancer metastasis.

Table 2.

Wnt/β-Catenin Signaling Inhibitors in Prostate Cancer.

Inhibitor	Mechanism of Action	Current Status	References
LGK974	Inhibits Wnt ligand secretion	Preclinical	⁴⁸
IWP-2	Inhibits Wnt receptor binding	Preclinical	⁴⁹
XAV939	Inhibits Tankyrase, stabilizing β-catenin degradation	Preclinical	⁵⁰
siRNA targeting β-catenin	Direct inhibition of β-catenin expression	Clinical trial stage	⁵¹

Epithelial-Mesenchymal Transition (EMT) Inhibition

The metastatic propagation of prostate cancer fundamentally depends on the process of EMT. Cell transformation in EMT makes tumors switch from expressing E-cadherin epithelial markers toward expressing vimentin and N-cadherin mesenchymal products. The development of prostate cancer cells through this transition allows them to break through neighboring tissue barriers while spreading to different parts of the body. The molecular elements of EMT have their roots in transcription factors Snail and Twist and ZEB1 because these regulatory proteins activate genes linked to cell motility along with invasion.¹³

Current Therapies

The Food and Drug Administration does not approve medications which specifically target EMT within prostate cancer cases. Various preclinical studies have shown that Cisplatin and taxane-based chemotherapy can cause some EMT-like transcriptional changes in the prostate cancer cell lines, which are capable of mediating adaptive responses to chemotherapy in vivo. These preclinical observations, however, do not mean that such agents have an adverse impact on clinical outcome on patients. Taxanes remain an essential part of evidence-based approaches to both hormone-sensitive and castration-resistant metastatic prostate cancer, including in combination therapy.⁵² Specific targeting of EMT is currently in the preclinical phase with little progress having been made due to the fact that this field is highly regulated by intricate systems and thus it is difficult to alter it without disrupting normal cellular activities. Transcription regulators related to EMT remain under active study as scientists develop multiple small molecules and antibodies to prevent their activity.

Emerging Therapies

Scientists currently test treatment approaches which focus on blocking transcription factors related to EMT including Snail, Twist, and ZEB1. Several small molecule inhibitors have demonstrated effective blocking of transcription factors’ activities during preclinical tests of prostate cancer. Curcumin has anti-EMT and anti-metastatic activity in a variety of in vitro models, but there are no clinical investigations to support its efficacy as a therapeutic agent in prostate cancer, eliminating its characterization as a validated anti-metastatic agent. The evidence that is available is all preclinical and exploratory.⁵³ Up to now, EMT-targeted therapy has not shown any clinical effectiveness in prostate cancer, and available agents, therefore, cannot be considered viable therapeutic options but solely as investigational agents. Research has explored the use of monoclonal antibodies that focus on N-cadherin molecules since these adhesion molecules drive EMT processes.¹⁶

The EMT process during prostate cancer metastasis is explained in Figure 7 through an examination of three essential transcription factors named Snail, Twist and ZEB1. The factors inhibit E-cadherin expression as a cell adhesion molecule so cells become more mobile leading to essential metastasis processes of migration and invasion. Cancer cell motility and invasiveness receive support through EMT enhancement functions of three key transcription factors Snail, Twist and ZEB1. Previous studies have shown that prostate cancer cells can detach from the primary site following loss of E cadherin regulatory factors decrease thereby enabling their spread through other tissues to distinct body regions.⁵⁴ Based on the diagram the downstream impact involves higher cell migration along with increased invasion that results in the formation of metastatic lesions. Examination of EMT-related transcription factors through these findings emphasizes their potential use as a treatment method to decelerate prostate cancer metastasis and limit treatment resistance.

Figure 7.

Targeting EMT in Prostate Cancer Metastasis.

Androgen Receptor (AR) Targeting

The hormone receptor known as the androgen receptor functions as a crucial element that drives prostate cancer expansion and evolution. During initial prostate cancer development tumors require the hormone testosterone together with other compounds known as androgens for their expansion. ADT stands as the primary treatment approach for prostate cancer since it either diminishes androgen levels or impedes their capability to bind with the AR receptor. The tumor of CRPC patients keeps developing after all androgen levels drop below measurable amounts.³⁸ AR-mediated resistance develops mainly through the coexistence of AR mutations together with AR splice variants because these elements enable the receptor to function without needed androgens.⁵⁵

Current Therapies

Medical professionals have received approval to treat CRPC patients with the androgen receptor antagonist drugs enzalutamide and abiraterone. The drugs inhibit androgen binding to AR receptors in the case of enzalutamide or disrupt the synthesis of androgens through abiraterone therapy.⁵⁶ The benefits from these therapies persist until patients build resistance to them which stresses the requirement for better AR-targeted treatment options.

Emerging Therapies

The medical community is actively researching different approaches to defeat resistance that develops against AR-targeted treatment strategies. These next-generation anti-androgens (darolutamide and apalutamide) show promise during clinical trials because they aim to block AR splice variants and stop AR activation.⁵⁷ Medical researchers are developing AR degradation therapies to combat resistance by enabling tumor cells to decrease their concentrations of the AR protein.⁵⁸ Modern therapy attempts to combat AR-expressing tumor cells through immunotherapy which presents a possible treatment solution for CRPC patients with inadequate treatment choices.

Discussion/Future Directions

Patients with metastatic prostate cancer face a key difficulty in oncology since present treatment methods deliver insufficient long-term results. Different molecular pathways like PI3K/AKT and Wnt/β-catenin and EMT intensify the metastatic process significantly. Biomedical researchers developed specific therapeutic strategies for cancer slowing and stopping based on their discoveries of these metabolic pathways. The clinical progress toward understanding metastatic drivers faces too many barriers which block the improvement of outcomes for patients with metastatic prostate cancer. A large percentage of the planned strategies outlined in this review are still in the experimental stages, and their clinical application is limited by the complexity of underlying pathways, the issue of toxicity, and the discrepancy between therapeutic effects in the preclinical trials.

Metastatic prostate cancer presents a major development challenge because the disease shows significant diversity among patients. The tumor cells that comprise prostate cancer demonstrate major differences both when comparing patients to each other and across the varying sections within one tumor. The treatment-resistant nature of such malignancies becomes difficult because the aggressive subclones can continue to evolve within individual tumors. In CRPC, different molecular subtypes remain even if a patient shows no response to androgen deprivation therapy.⁵⁹ Personalized medicine approaches become crucial because every cancer patient shows distinct molecular features that need individualized treatment.

New treatment methods that focus on PI3K/AKT and Wnt/β-catenin pathways show promise yet struggle against multiple signaling network interactions. AKT inhibitor treatments demonstrated early clinical trial success yet most patients eventually develop resistance to the treatment. The activation of alternative pathways like Mitogen Activated Protein Kinase (MAPK) or PI3K occurs in tumors when resistance develops by circumventing the effects of AKT inhibitors to protect and advance tumor growth.⁶⁰ Combination therapies are being investigated as a strategy to overcome this resistance. Researchers believe enzalutamide AR signaling inhibitors used in combination with AKT inhibitors have potential to improve prostate cancer metastatic treatment effectiveness by preventing compensatory pathway activation.⁵⁷

Research efforts focus currently on the study of inhibiting EMT. The transformation of prostate cancer cells into mesenchymal cells serves as an essential step for metastasis because it enables detachment from origins and subsequent tissue penetration and distant travel. EMT remains difficult to target because multiple elements including Snail, Twist, and ZEB1 transcription factors and TGF-β cytokines control its highly volatile process. Small molecule inhibitors targeting these factors remain in pre-clinical development, and translation to clinical use has been slow because medical scientists face problems when trying to target these pathways effectively without disrupting normal cellular processes. Prostate cancer cells become more difficult to target because they develop treatment adaptability and move between epithelial and mesenchymal states.¹³

Prostate cancer metastasis regulation mainly depends on the Wnt/β-catenin signaling pathway because it controls the activity of CSCs which are linked to original tumor development and disease progression and recurrence. Cancer stem cell self-renewal along with metastasis decreased significantly after β-catenin inhibition in animal models. Wnt pathway inhibitors remain at an early developmental phase for clinical use because scientists need to solve specific inhibitory issues and unwanted byproduct affects. The normal tissue regenerative process depends on Wnt signaling so general pathway inhibition presents a risk of undesirable side effects in patients.⁶¹ Nanoparticle based systems, tankyrase inhibitors, and Wnt receptor antagonists show potential as more selective therapeutic approaches for Wnt/β-catenin signaling in metastatic prostate cancer.⁶²

Research should focus on combining immunotherapy with the treatment of metastatic prostate cancer. The treatment of melanoma and non-small cell lung cancer along with other cancers recently experienced transformation because of immune checkpoint inhibitors which target PD-1 and PD-L1. The outcomes of immune checkpoint inhibitor treatment in prostate cancer patients remain limited especially when treating advanced stage disease. Scientists now propose that immune checkpoint blockade activity against prostate cancer becomes more potent when combined with AR inhibitors and chemotherapy to transform tumor microenvironments toward creating better immune responses.⁶³ The results of immunotherapy treatments may improve through the discovery of specific targets within immune checkpoints and tumor antigens that exist exclusively in metastatic prostate cancers.

Progression in clinical management of metastatic prostate cancer can be achieved through the development of new liquid biopsy technologies for both diagnosis and monitoring purposes. Patients can receive genetic alteration analysis and active treatment monitoring through liquid biopsy procedures which examine circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) or exosomes. Laboratory tests that use small blood samples demonstrate potential to reveal molecular cancer changes in metastasis while confirming therapy choices and disease evolution without requiring primary tissue acquisitions.⁶⁴ The implementation of liquid biopsy in clinical settings would lead to better dynamic and precise knowledge about metastatic prostate cancer which could detect treatment-resistant diseases at an earlier stage.

Researchers focus on developing new drug delivery platforms which aim to enhance the accuracy and therapeutic outcome of metastatic prostate cancer management strategies. Nanoparticle-based delivery systems utilize small molecule inhibitors through directed delivery to tumor sites which both cuts down off-target responses and increases drug amounts found in tumors.⁶⁵ The systems enable the administration of combination therapy through delivering multiple drugs which target distinct molecular pathways in one treatment protocol thus achieving improved effects and minimizing adverse side effects.

Despite these advances, the biological complexity of metastatic prostate cancer continues to challenge effective treatment and patient resistance to treatments. Advancements in treatment methods for prostate cancer will likely use molecular profiling together with simultaneous administration of multiple targeting therapies while advancing drug delivery techniques and biomarker detection systems. Research into prostate cancer metastasis biology leads the way for developing advanced targeted treatments which will benefit metastatic disease patients.

Over the last four years, a succession of landmark end-of-life clinical trials have significantly changed the treatment environment of advanced and metastatic prostate carcinoma, consequently highlighting the need and significance of precision-focused treatment. The Phase 1-III Trial of 177Lu-PSMA-617 in Taxnae-Naive mCRPC Patients (PSMAfore)⁶⁶ and Lutetium-177 PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Trial (VISION)⁶⁷ showed that the use of luetium-177-psma-617 radioligand therapy provides a statistically significant overall survival and patient-reported quality of life outcome in patients with PSMA-positive At the same time, the Phase 11 Trial that is Comparing Olaparib Plus Abiraterone in mCRPC (PROpel)⁶⁸ and Phase 11 Trial of talazoparib Plus Enzalutamide in mCRPC (TALAPRO-2)⁶⁹ concluded that the use of PARP inhibitors, olaparib or talazoparib, as the addition to the current androgenreceptor blockade of signaling is associated with better progression Further confirmation of the triplet combination of darolutamide, androgen-deprivation therapy, and docetaxel compatibility as an emerging standard of care in metastatic hormone-sensitive disease was made through the Phase/III Trial of Darolutamide Plus ADT and Docetaxel in metastatic hormone-sensitive prostate cancer (ARAS Edwards).⁷⁰ These data represent cumulatively the synthesis of genomic knowledge and therapeutic accuracy, and confirm the translation of molecular pathways into clinical value.

A series of phase III trials that have progressively re-defined clinical paradigms has enabled quick application of molecular insight into clinical practice. Both VISION and PSMAfore trials confirmed lumetium-177-PSMA-617 radioligand therapy as a survival-prolonging modality of PSMA-positive metastatic castration-resistant prostate cancer. In addition, the PROpel and TALAPRO-2 trials supported the fact that the combination of PARP inhibitors, be it olaparib or talazoparib, with standard androgen-receptor-modulating agents significantly enhances the radiographic progression-free survival, particularly in neoplasms with homologous-recombination repair defects. Together with guideline updates expected to be issued during 20242025, these findings are shedding light on the role of DNArepair stratification in guiding therapeutic decision-making and highlighting the increasing clinical relevance of overall molecular profiling.

Conclusion

The future of prostate cancer treatment, particularly for metastatic disease, hinges on a deeper understanding of the molecular mechanisms driving metastasis and resistance to conventional therapies. Treatments that employ androgen deprivation and chemotherapy have offered some benefits yet these measures demonstrate their restricted scope against metastatic disease which demonstrates a critical requirement for more specific intervention methods. The molecular processes of PI3K/AKT pathway and Wnt/β-catenin pathway and EMT functions together as main elements in metastasis formation which expands opportunities for developing therapeutic treatments. The hindering factors of therapeutic progress are the obstacles to treatment resistance along with tumor heterogeneity and unwanted therapeutic effects. New medications targeting these pathways namely AKT inhibitors and Wnt signaling inhibitors together with EMT disruptive methods are advancing in clinical trials with preclinical success. Effective metastatic spread control could be achieved through multiple pathway simultaneous targeting through combination therapy approaches. The combination of targeted therapies with immunotherapy and biomarker-dependent care and liquid biopsy tools will transform individualized therapy methods by enabling enhanced disease progression monitoring and superior therapeutic selection alternatives. The complex nature of prostate cancer metastasis together with resistance mechanisms produces ongoing difficulties when managing this condition. Further research alongside the creation of new drug delivery platforms and targeted pharmaceuticals alongside combined therapeutic approaches represent essential methods to enhance outcome results for patients with metastatic prostate cancer. Person-centered care strategies along with modern innovations in nanomedicine and biomarker assessment will combine genetic and molecular data with environmental aspects to create advanced and harmless therapeutic options for metastatic prostate cancer treatment in the near future.

Footnotes

List of Abbreviations

Acknowledgements

We thank the Covenant University Center for Research, Innovation, and Discovery (CUCRID), Nigeria, for the payment of the article processing charges (APC), and the Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE) for their support.

ORCID iDs

Emeka Eze Joshua Iweala

Chukwuemeka Pius Nwokoro

Ethics Statement

This is a review article and does not involve any human participants or animal studies. Therefore, an ethics approval statement is not applicable.

CRediT Authorship Contribution Statement

Emeka Eze Joshua Iweala: Conceptualization, Supervision. Nwokoro Chukwuemeka Pius: Conceptualization, Writing – original draft, Writing – review & editing, Visualization.

Funding

This work was supported by the Covenant University Center for Research, Innovation, and Discovery (CUCRID) and the Covenant Applied Informatics and Communication Africa Centre of Excellence (CApIC-ACE), Nigeria.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Ayeni

Bajepade

Akanni

Pirisola

Oluwajembola

Chinedu

. The association of steroid 5-alpha reductase type-II gene polymorphisms (A49T and V89L) with prostate cancer risk in African population: a systematic review and meta-analysis. Sci Afr. 2024;26:e02370.

Xue

Guo

Zhou

, et al. Age-sex-specific burden of urological cancers attributable to risk factors in China and its provinces, 1990–2021, and forecasts with scenarios simulation: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Reg Health West Pac. 2025;56:101517.

Rotimi

Salako

Jibrin

Oyelade

Iweala

EEJ

. Gene expression profiling analysis reveals putative phytochemotherapeutic target for castration-resistant prostate cancer. Front Oncol. 2019;9.

Agbetuyi-Tayo

Gbadebo

Rotimi

. Advancements in biomarkers of prostate cancer: a review. Technol Cancer Res Treat. 2024;23.

Hashemi

Taheriazam

Daneii

, et al. Targeting PI3K/Akt signaling in prostate cancer therapy. J Cell Commun Signal. 2022;17(3):423–443. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409967/

Shorning

Dass

Smalley

Pearson

. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. Int J Mol Sci. 2020;21(12):4507.

Kaplan

Zielske

Ibrahim

Cackowski

. Wnt and β-catenin signaling in the bone metastasis of prostate cancer. Life. 2021;11(10):1099.

Wang

Singhal

Qiao

, et al. Wnt signaling drives prostate cancer bone metastatic tropism and invasion. Transl Oncol. 2020;13(4):100747.

Cao

Kyprianou

. Mechanisms navigating the TGF-β pathway in prostate cancer. Asian J Urol. 2015;2(1):11–18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645057/

10.

Thompson-Elliott

Johnson

Khan

. Alterations in TGFβ signaling during prostate cancer progression. Am J Clin Exp Urol. 2021 Aug 25 [cited 2025 Apr 30];9(4):318. https://pmc.ncbi.nlm.nih.gov/articles/PMC8446771/

11.

Yang

, et al. Molecular classifications of prostate cancer: basis for individualized risk stratification and precision therapy. Ann Med. 2023;55(2).

12.

Fontana

Mestre-Farrera

Yang

. Update on epithelial-mesenchymal plasticity in cancer progression. Annu Rev Pathol: Mech Dis. 2024;19(1):133–156.

13.

Nauseef

Henry

. Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle? Nat Rev Urol. 2011;8(8):428–439. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858788/

14.

Yang

. A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 2015;9(4):317–324.

15.

Khan

Hamid

Adhami

Lall

Mukhtar

. Role of epithelial mesenchymal transition in prostate tumorigenesis. Curr Pharm Des. 2015;21(10):1240–1248.

16.

Loh

Chai

Tang

, et al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells. 2019;8(10):1118.

17.

Cai

Moten

Peng

, et al. The Skp2 pathway: a critical target for cancer therapy. Semin Cancer Biol. 2020;67:16–33.

18.

Usman

Waseem

Nguyen

TKN

, et al. Vimentin is at the heart of epithelial mesenchymal transition (EMT) mediated metastasis. Cancers (Basel). 2021;13(19):4985.

19.

Cao

Wang

Leng

. Aberrant N-cadherin expression in cancer. Biomed Pharmacother. 2019;118:109320.

20.

Wang

Shi

Chai

Ying

Zhou

. The role of snail in EMT and tumorigenesis. Curr Cancer Drug Targets. 2013;13(9):963–972.

21.

Akhtar

Syed

Lall

Mirza

Mukhtar

. Targeting epithelial to mesenchymal transition in prostate cancer by a novel compound, plectranthoic acid, isolated from Ficus microcarpa. Mol Carcinog. 2018;57(5):653–663.

22.

Glaviano

Song

Julia

, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1).

23.

Montanari

Rossetti

Cavaliere

, et al. Epithelial-mesenchymal transition in prostate cancer: an overview. Oncotarget. 2017;8(21):35376–35389. http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=15686

24.

Gonzalez-Avila

Sommer

Mendoza-Posada

Ramos

Garcia-Hernandez

Falfan-Valencia

. Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit Rev Oncol Hematol. 2019;137:57–83. https://www.ncbi.nlm.nih.gov/pubmed/31014516

25.

Jamaspishvili

Berman

Ross

, et al. Clinical implications of PTEN loss in prostate cancer. Nature Rev Urol. 2018;15(4):222–234. https://www.nature.com/articles/nrurol.2018.9

26.

Sun

Zhang

, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6(1):1–17. https://www.nature.com/articles/s41392-021-00828-5

27.

Liu

Cheng

Roberts

Zhao

. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discovery. 2009;8(8):627–644. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142564

28.

Nitulescu

Van De Venter

Nitulescu

, et al. The Akt pathway in oncology therapy and beyond. Int J Oncol. 2018;53(6).

29.

Liu

Xiao

, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7(3):3. https://www.nature.com/articles/s41392-021-00762-6

30.

Song

Gao

Bao

, et al. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol. 2024;17(1).

31.

Schneider

Logan

. Revisiting the role of Wnt/β-catenin signaling in prostate cancer. Mol Cell Endocrinol. 2018;462:3–8.

32.

Krishnamurthy

Kurzrock

. Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745276/

33.

Stamos

Weis

. The β-catenin destruction complex. Cold Spring Harbor Perspect Biol. 2013;5(1):a007898.

34.

Wang

Chen

. Wnt/β-catenin signal transduction pathway in prostate cancer and associated drug resistance. Discov Oncol. 2021;12(1).

35.

Karantanos

Corn

Thompson

. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32(49):5501–5511. https://pubmed.ncbi.nlm.nih.gov/23752182/

36.

Zhu

Kyprianou

. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J. 2010;24(3):769–777.

37.

Linder

van der Poel

Bergman

Zwart

Prekovic

. Enzalutamide therapy for advanced prostate cancer: efficacy, resistance and beyond. Endocr Relat Cancer. 2019;26(1):R31–R52. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215909/

38.

Chatterjee

. The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer. Mol Cell Biochem. 2003;253(1-2):89–101. https://www.ncbi.nlm.nih.gov/pubmed/14619959

39.

Liang

Zhou

, et al. Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy. Ann Med. 2024;57(1).

40.

Zhang

Nie

, et al. Cancer stem-like cells stay in a plastic state ready for tumor evolution. Neoplasia. 2025;61:101134.

41.

Owonikoko

Khuri

. Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation. Am Soc Clin Oncol Educ Book. ASCO American Society of Clinical Oncology Meeting. 2013;33:e395–e401. doi:10.1200/EdBook_AM.2013.33.e395. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821994/

42.

Wang

, et al. Important roles of PI3K/AKT signaling pathway and relevant inhibitors in prostate cancer progression. Cancer Med. 2024;13(21).

43.

Castel

Toska

Engelman

Scaltriti

. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer. 2021;2(6):587–597.

44.

Rascio

Spadaccino

Rocchetti

, et al. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an updated review. Cancers (Basel). 2021;13(16):3949. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394096/

45.

Wylaź

Kaczmarska

Pajor

Hryniewicki

Gil

Dulińska-Litewka

. Exploring the role of PI3K/AKT/mTOR inhibitors in hormone-related cancers: a focus on breast and prostate cancer. Biomed Pharmacother. 2023;168:115676. https://www-sciencedirect-com-443.web.bisu.edu.cn/science/article/pii/S0753332223014749

46.

Park

Jong Kim

. A new wave of targeting “undruggable” wnt signaling for cancer therapy: challenges and opportunities. Natl Cent Biotechnol Inf. 2023;12(8):1110.

47.

Mariotti

Pollock

Guettler

. Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding. Br J Pharmacol. 2017;174(24):4611–4636.

48.

Liu

Pan

Hsieh

, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA. 2013;110(50):20224–20229. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864356/

49.

García-Reyes

Witt

Jansen

, et al. Discovery of inhibitor of Wnt production 2 (IWP-2) and related compounds as selective ATP-competitive inhibitors of casein kinase 1 (CK1) δ/ε. J Med Chem. 2018;61(9):4087–4102. https://pubmed.ncbi.nlm.nih.gov/29630366/

50.

Wang

Jia

Wei

Chua

. Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells. Oncotarget. 2015;6(28):25390–25401.

51.

Zeng

Apte

Cieply

Singh

Monga

SPS

. siRNA-mediated β-catenin knockdown in human hepatoma cells results in decreased growth and survival. Neoplasia. 2007;9(11):951–959.

52.

Seo

Kang

Cho

. The role of epithelial–mesenchymal transition-regulating transcription factors in anti-cancer drug resistance. Arch Pharmacal Res. 2021;44(3):281–292. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009775/

53.

Chuang

Chiou

Hsu

. Recent advances in transcription factors biomarkers and targeted therapies focusing on epithelial–mesenchymal transition. Cancers (Basel). 2023;15(13):3338. https://www-mdpi-com-s.web.bisu.edu.cn/2072-6694/15/13/3338

54.

Huang

Hong

Wei

. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol. 2022;15(1).

55.

Cao

Zhan

Dong

. Emerging data on androgen receptor splice variants in prostate cancer. Endocr Relat Cancer. 2016;23(12):T199–T210.

56.

Rathkopf

Scher

. Androgen receptor antagonists in castration-resistant prostate cancer. Cancer J. 2013;19(1):43–49.

57.

Wang

, et al. Novel hormone therapies for advanced prostate cancer: understanding and countering drug resistance. J Pharm Anal. 2025:101232.

58.

Kregel

Wang

Han

, et al. Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment. Neoplasia (New York, NY). 2020;22(2):111–119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957805/

59.

Leslie

Soon-Sutton

Sajjad

Siref

. Prostate cancer. Nih.gov. StatPearls Publishing; 2023, https://www.ncbi.nlm.nih.gov/books/NBK470550/ .

60.

Garg

Ramisetty

Nair

, et al. Strategic advancements in targeting the PI3K/AKT/mTOR pathway for breast cancer therapy. Biochem Pharmacol. 2025;236:116850. https://www-sciencedirect-com-443.web.bisu.edu.cn/science/article/pii/S0006295225001121

61.

Banerjee

Kapse

Siddique

, et al. Therapeutic implications of cancer stem cells in prostate cancer. Cancer Biol Med. 2023:1–20.

62.

Zhao

Luo

, et al. Blocking the WNT/β-catenin pathway in cancer treatment: pharmacological targets and drug therapeutic potential. Heliyon. 2024:e35989.

63.

Chen

, et al. Synergistic effects of immunotherapy and adjunctive therapies in prostate cancer management. Crit Rev Oncol Hematol. 2024;207:104604.

64.

Bin Riaz

Wang

Kohli

. Liquid biopsy approach in the management of prostate cancer. Transl Res. 2018;201:60–70.

65.

Adekiya

Owoseni

. Emerging frontiers in nanomedicine targeted therapy for prostate cancer. Cancer Treat Res Commun. 2023;37:100778.

66.

Fizazi

Chi

Shore

, et al. Final overall survival and safety analyses of the phase 3 PSMAfore trial of [177Lu]Lu-PSMA-617 versus change of androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2025;36(11):1319–1330.

67.

Morris

Castellano

Herrmann

, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227–1239.

68.

Saad

Clarke

Oya

, et al. Olaparib plus Abiraterone versus placebo plus Abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094–1108.

69.

Azad

Fizazi

Matsubara

, et al. Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: safety analyses from the randomized, placebo-controlled, phase III TALAPRO-2 study. Eur J Cancer. 2024;213:115078.

70.

Hussain

Tombal

Saad

, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol. 2023;41(20).