Prostate cancer (PCa) ranks as the fourth most commonly diagnosed cancer globally, accounting for 7.3% of all cases. In 2020, PCa held the position of the second most prevalent cancer (at 14.1%) and the fifth leading cause of cancer-related mortality (at 6.8%) among men [1]. Factors such as advanced age, African descent, and a family history of the disease are associated with poorer prognoses for PCa [2].

Treatment for PCa primarily involves androgen deprivation therapy (ADT), androgen receptor (AR)-signaling inhibitors (ARSIs), and chemotherapy. Following initial hormone therapy, metastatic castration-sensitive PCa (mCSPC) often progresses to metastatic castration-resistant PCa (mCRPC) within approximately 1–2 years. The median survival time and cancer-specific mortality for mCRPC are 22 months (95% confidence interval [CI]: 21.0–22.9) and 30 months (95% CI: 28.3–31.7), respectively ^[3][4]. In one study, the 1- and 5-year survival rates for mCRPC were estimated at 58, 37, and 58% and 17, 4, and 9% in German, Swedish, and US cohorts, respectively ^[4][5]. In another study, the median overall survival (OS) for chemotherapy-naïve mCRPC was significantly longer in the ARSI group (treated with abiraterone acetate or enzalutamide; 34.7 and 35.3 months, respectively) than in the placebo group ^[5][6][6,7].

Recently, precision medicine targeting driver genes, such as treatment employing poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA mutations identified through companion diagnostics, has been realized. Next-generation sequencing (NGS) technology has facilitated comprehensive and exhaustive genome analysis, revealing a multitude of genetic mutations associated with cancer initiation and progression. Furthermore, NGS has enabled routine clinical examination of individual genetic abnormalities. Consequently, personalized treatments based on genetic anomalies have been developed, even in the context of PCa, with accumulating evidence supporting this approach. Recent reports have highlighted the utility of Decipher Prostate testing in determining the treatment approach for recurrence after radical prostatectomy ^[7][9]. Despite extensive genome-wide sequencing studies on PCa, no biomarker has surpassed PSA for several decades.

2. Genomic Alterations

In PCa, the involvement of driver genes is highly diverse in terms of both carcinogenesis and disease progression. This diversity varies significantly among different cases as well as across various stages of PCa. Considering the variation in driver genes, precision medicine assumes profound significance in the context of PCa. The most prevalent genetic anomalies observed in PCa include point mutations in genes such as SPOP, FOXA1, and TP53, as well as copy number alterations (CNAs) in AR, MYC, RB1, PTEN, CHD1, and fusion genes associated with the ETS (E26 transformation-specific) family ^{[8][9][10][11][12][13][14][15]}[10,11,12,13,14,15,16,17]. Alterations in pathways involving AR, TP53, the cell cycle, and MYC are strongly associated with the development of castration resistance and OS. By contrast, alterations in the Wnt pathway and SPOP mutations are indicative of a more favorable prognosis ^{[16][17][18][19][20][21]}[18,19,20,21,22,23]. Notably, changes in AR and PI3K/Akt pathway components appear to result from continuous systemic therapy ^[22][23][24,25]. The prevalence of specific alterations varies in different clinical contexts. For instance, alterations in TP53 (35% vs. 29%), BRCA2 (10% vs. 4%), PIK3CA (8% vs. 2%), RB1 (7% vs. 3%), and APC (11% vs. 9%) are more frequent in high-volume diseases than in low-volume diseases. Alterations in CDK12, PTEN, and FOXA1 are similarly detected between CSPC and CRPC, whereas those in ATM and RB1 exhibit a similar prevalence between de novo and recurrent metastatic disease, with CDK12 (6% vs. 1%) and FOXA1 (17% vs. 10%) alterations more commonly observed in the de novo metastatic state. The PI3K/Akt pathway is affected in 35–40% of mCSPC cases ^{[16][17][18][19][20][21][24][25][26][27][28]}[18,19,20,21,22,23,28,31,32,33,34].  In mCRPC, the most frequently aberrant genes include AR (62.7%), the ETS family (56.7%), TP53 (53.3%), and PTEN (40.7%). The frequency of alterations in these genes is significantly higher than that observed in localized cancer ^[29][36]. In mCRPC, non-AR-related clinically actionable alterations include aberrations in the PI3K/Akt pathway (49%), DNA repair pathway (19%), RAF kinases (3%), CDK inhibitors (7%), and Wnt pathway (5%) ^[29][36]. Notably, alterations in AR, TP53, RB1, PTEN, and ATM are enriched in mCRPC when compared with those in mCSPC ^[24][28].

2.1. Fusion Genes from the ETS Family

Among the most prevalent genomic alterations in PCa are fusions involving androgen-regulated promoters with ERG and other members of the ETS family of transcription factors. ETS fusions are observed in over 50% of cases ^{[8][29][30][31]}[10,36,38,39]. In particular, the TMPRSS2–ERG fusion represents the most frequent molecular alteration in PCa ^[32][40], occurring in 40–50% cases, equivalent to >100,000 cases annually in the United States alone ^[33][41]. Notably, Asian patients with PCa exhibit fewer TMPRSS2–ERG fusions than do Caucasian or African-American patients ^[34][35][36][42,43,44]. TMPRSS2 expression is upregulated by androgenic hormones in PCa cells but downregulated in androgen-independent PCa tissue ^[36][44]. Genetic polymorphisms associated with PCa susceptibility may vary by race and ethnicity.

2.2. AR and AR-Related Genes

The dysregulation of AR and AR pathway-related genes plays a central role in PCa pathogenesis. Abnormalities in the AR pathway include gene amplifications, mutations, splicing variants, and ligand-independent AR activity. Furthermore, these abnormalities can result from coding regions as well as AR enhancer region amplifications and genomic structural rearrangements capable of producing constitutively active truncated AR isoforms, notably AR splice variant 7 (AR-V7) ^[37][50]. Over 70% of PCa cases exhibit AR pathway aberrations, including those involving SPOP or FOXA1, with the majority resulting from direct alterations affecting AR through amplifications and mutations ^[29][36]. Alterations in androgen receptor signaling are more frequently observed in metastatic samples, with AR amplification or mutation being the most common alteration (50–80%). SPOP mutations, while present, are relatively less frequent in metastatic samples ^{[8][29][38][39]}[10,36,51,52]. AR alterations are rarely observed prior to ADT, although they are enriched in patients with mCRPC who have a higher disease burden and prior exposure to ARSIs ^[40][53]. By contrast, changes in AR copy number status are not evident in patients treated with docetaxel or cabazitaxel ^[41][42][54,55]. SPOP plays a role in protein degradation by acting as a substrate adaptor, enabling ubiquitination by the Cullin3–RING complex ^[43][62]. In PCa, SPOP functions as a tumor-suppressor gene by promoting the degradation of multiple oncogenic substrates, including AR and ERG ^[44][45][63,64]. SPOP mutations represent the most common point mutations in localized PCa ^[8][10][10,12]. The frequency of SPOP mutations in localized disease (10–15%) and metastatic PCa (5–10%) aligns with the observation of a more favorable disease prognosis in de novo mCSPC ^[21][23]. Alterations in SPOP are enriched in locoregional and early-stage disease; therefore, tumors with SPOP mutations may exhibit increased sensitivity to ADT ^[10][24][46][12,26,28].

2.3. TP53

When comparing clonal alterations between a matched primary localized tumor and a subsequent metastatic tumor from the same patient, tumors acquired at a later stage typically exhibit a higher mutation count than do tumors acquired at an earlier stage. TP53 alterations emerge early in affected patients and are present in all tumors from the same patient. TP53 mutations are clonal, even in cases of both primary localized and subsequent metastatic PCa ^[24][28]. A high frequency of TP53 alterations is observed in primary localized tumors, consistent with prior reports of aggressive behavior of PCa caused by TP53 alterations ^[47][48][49][66,67,68]. The timing of TP53 alterations in tumors, specifically whether these alterations are present in tumors early in their evolution or acquired later during disease progression, remains uncertain. Somatic alterations in BRCA2 have been identified in matched tumors, suggesting that somatic loss-of-function alterations in this gene occur early in tumorigenesis. By contrast, alterations in AR do not occur early in matched samples, which is consistent with treatment-related changes that promote castration resistance ^[24][28].

2.4. Mitogen-Activated Protein Kinase (MAPK) Pathway

Genes within the MAPK pathway are affected in 25% of tumors ^[8][10]. The presence of RAF kinase fusions in 3% of individuals with mCRPC suggests the potential utility of pan-RAF inhibitors or MEK inhibitors ^[29][36].

2.5. PI3K/Akt Pathway

Alterations in the PI3K/Akt pathway constitute the second most frequently observed pathway aberration in metastatic PCa ^{[8][29][50][51]}[10,36,69,70]. The PI3K/Akt pathway may be antagonized by several phosphatases, including PTEN and PHLPP. PI3K activation results in the phosphorylation of AKT and its downstream genes, including the mammalian target of rapamycin (mTOR). Phosphorylated AKT is an indicator of PI3K/Akt pathway activation ^[52][53][71,72], and AKT activates nuclear factor-κB (NF-κB) signaling in CRPC, with levels of NF-κB being higher in castration-resistant cell lines than in androgen-dependent cell lines ^[54][73]. PTEN, which leads to the downstream activation of the PI3K/Akt and AR signaling pathways, plays a crucial role in tumor suppression, and its loss is associated with poorer clinical outcomes in patients with mCRPC ^{[16][40][55][56]}[18,53,74,75]. Considering that PTEN-deleted tumors may rely on PIK3CB owing to feedback inhibition from PIK3CA, the simultaneous loss and mutation of PTEN and PIK3CB could result in increased PI3K/Akt pathway activity. This observation suggests the existence of a subset of tumors for which a combination of PI3K and androgen signaling inhibition might be effective. In the context of the PI3K/Akt pathway, specific inhibitors targeting PIK3CB may be beneficial for individuals with mutations, amplifications, and/or fusions involving the related gene.

2.6. NF-κB Signaling

The NF-κB/Rel proteins include NF-κB2 p52/p100, NF-κB1 p50/p105, c-Rel, RelA/p65, RelB, and others. These proteins function as dimeric transcription factors, primarily regulating the transcription of genes involved in a wide range of biological processes such as apoptosis, angiogenesis, inflammation response, cell survival, inflammation, stress response, B-cell development, and lymphoid tissue formation ^{[57][58][59][60][61][62]}[79,80,81,82,83,84]. The activation of NF-κB (p65) and Sonic Hedgehog pathways in PCa is positively correlated, and the overexpression of NF-κB(p65), SHh, and GLI1 is observed in aggressive PCa tissue cores featuring a high Gleason score and advanced clinical stage. These pathways play key roles in the progression of advanced PCa and are potential targets for therapeutic intervention ^[63][85]. The involvement of NF-κB signaling in the onset and maintenance of CRPC is considerable, irrespective of whether it is due to abnormal AR activity or AR-independent mechanisms ^[64][86]. Moreover, NF-κB plays a crucial role in the development of treatment resistance and metastasis in PCa. Specifically, the RelB-activated noncanonical NF-κB pathway could prolong and enhance NF-κB activity ^[65][87].

2.7. Cell Cycle Pathway

RB1 loss is detected in 21% of PCa cases ^[29][36]. Focal amplifications involving CCND1 (9%), as well as less frequent (<5%) events affecting CDKN2A/B, CDKN1B, and CDK4, are observed in mCRPC ^[29][36]. Disruptions in the cell cycle, such as CCND1 amplification or CDKN2A/B loss, may lead to an increased responsiveness to CDK4 inhibitors, as observed in other tumor types ^[66][27]. Pre-clinical findings indicate that selectively targeting CDK4/6 represents a therapeutic approach for both early-stage and advanced prostate PCa ^[67][92]. Mutations or deletions of TP53 and RB1 are more prevalent in metastatic than in localized PCa ^[8][29][10,36], and these alterations are associated with a poorer clinical outcome and aggressive behavior ^{[47][48][68][69][70]}[35,66,67,93,94].

2.8. DNA Repair Pathway

Alterations in the DNA repair pathway are more frequent in mCRPC than in localized PCa or CSPC ^[8][29][10,36]. Genetic abnormalities associated with the DNA damage response (DDR) are observed in approximately 23–28% of mCRPC cases, including both germline and somatic variants ^{[8][9][18][24][71][72]}[10,11,20,28,29,30].

2.8.1. HRR Genes

Among common gene abnormalities, BRCA2 and ATM mutations constitute a significant majority ^[24][28]. In advanced PCa, BRCA2 (7–13%), BRCA1 (0–1%), ATM (5–7%), and CDK12 (4–6%) exhibit frequent mutations ^{[29][38][39][73]}[36,51,52,95]. The prevalence of pathological variants in BRCA1/2 and ATM varies across different stages of PCa ^{[8][29][74][75]}[10,36,76,96]. ATM alterations are associated with a poor prognosis; germline mutations are linked to higher tumor grades and lethal PCa ^[76][77][78][97,98,99]. CDK12 alterations are associated with aggressive clinical features and a poor prognosis in mCRPC ^[79][100]. In a study of PCa patients who underwent radical prostatectomy or localized radiation therapy, both metastasis-free survival and disease-specific survival were significantly shorter in patients with BRCA mutations than in non-carriers ^[80][101]. In localized PCa, BRCA2 germline mutations are associated with early-onset, high-grade tumors and a poor prognosis ^[80][81][101,102]. BRCA2 alterations are enriched in mCRPC relative to their frequency in mCSPC ^[68][35].

2.8.2. MMR Genes and Microsatellite Instability (MSI)

Tumors with MMR gene deficiencies or MSI often exhibit an augmented antitumor immune response characterized by an increased density of tumor-infiltrating lymphocytes (TILs) ^[82][83][114,115]. This phenomenon is attributed to elevated mutation rates and enhanced levels of neoantigens in MMR-deficient tumors. Such neoantigens arise through various mechanisms, including mutant peptides, frameshift mutations, and insertions or deletions (indels) in coding microsatellites ^[84][85][116,117]. These neoantigens are presented on the cell surface by MHC-I molecules, facilitating the T-cell-mediated elimination of tumor cells. Approximately 3–8% of PCa cases, with a germline mutation rate of approximately 1%, are linked to the deficiency of MMR genes, including MSH2, MSH6, PMS2, and MLH1. Such deficiency leads to hypermutation, MSI, and characteristic trinucleotide mutational signatures ^{[24][29][86][87][88][89][90][91]}[28,36,118,119,120,121,122,123]. MMR genes play crucial roles in the recognition and repair of incorrect insertions, deletions, and base misincorporations during DNA replication or recombination ^[92][124].

3. Immune Environment

In the context of PCa, the immune environment and hormone therapy involve macrophages/antigen-presenting cells (APCs), CD8-positive cytotoxic T lymphocytes, CD4-positive helper T lymphocytes, and natural killer (NK) cells, all of which recognize and target cancer cells, contributing to antitumor immunity. Several studies have reported on the expression of these cells within prostate tissues; notably, fewer TILs have been identified in poorly differentiated PCa than in benign prostatic hyperplasia, suggesting a potential link between immune cell deficiency and cancer progression. The infiltration of these immune cells within the tumor microenvironment of PCa tissue has also been associated with prognosis; patients with PCa and a higher number of infiltrating TILs tend to have better outcomes than those with fewer infiltrating TILs ^[93][94][95][134,135,136]. The examination of CD68-positive tumor-infiltrating macrophages (TAMs) in radical prostatectomy specimens of patients with PCa revealed that cases with a higher number of infiltrating cells were associated with a significantly worse prognosis for PSA recurrence than those with fewer infiltrating cells ^[96][137].

4. Epigenetic Modifications

Epigenetic traits represent inheritable characteristics resulting from chromosomal alterations or DNA modifications without alteration of the DNA sequence ^[97][145]. Epigenetic modifications, including acetylation, methylation, ubiquitination, and phosphorylation, play pivotal roles in transcription, DNA repair, and replication ^[98][146]. Epigenetic regulation is a dynamic and reversible process involving the addition of epigenetic marks to histones or DNA, the recognition or recruitment of these marks, and the removal of these marks by epigenetic writers, readers, and erasers, respectively. PCa is associated with alterations in DNA methylation, histone modification, chromatin accessibility, and 3D chromatin structure. Such changes contribute to disease development and progression by influencing gene expression, promoting cellular plasticity, and facilitating CRPC emergence under treatment pressure. The dysregulation of chromatin and epigenetics confers the complete range of cancer hallmarks by altering transcriptional regulation, mediating all defined hallmarks of cancer, and promoting cancer cell plasticity ^[99][147].

4.1. DNA Methylation

The contribution of DNA methylation to PCa development was first reported in the early 1990s ^[100][161]. Approximately 22% of tumors in PCa are associated with hypermethylation ^[101][162]. DNA methylation is linked to gene silencing and occurs when a methyl group is added to the C5 position of the cytosine residues in CpG dinucleotides ^[102][163]. DNMT (DNA methyltransferase) enzymes catalyze the addition of 5-methyl cytosine to DNA, which can be removed by DNA demethylases from the ten-eleven translocation (TET) family ^[103][164]. In addition, approximately 60% of all gene promoters are associated with CpG islands ^[104][165]. Cytidine methylation of regulatory sequences near GSTP1, which encodes an enzyme responsible for safeguarding DNA against oxidants and carcinogens, has been associated with prostate tumorigenesis ^[105][171]. In PCa, GSTP1 is methylated in its promoter region, leading to the diminished expression of GSTP1 in tumor cells. Hypermethylation of the GSTP1 promoter occurs in approximately 75% of pre-invasive high-grade prostatic intraepithelial neoplasms and in over 90% of prostate tumors and persists through all stages of PCa progression ^[106][172].  Promoter hypermethylation can lead to the silencing of not only tumor-suppressor genes but also key receptors, such as AR and ESR1. Additionally, cell adhesion genes (such as CD44 or CDH1), cell cycle genes (such as CCND2, CDKN1B, or SFN), and apoptosis-related genes (such as ASC, BCL2, DAPK, or PTGS2) can be affected by this process ^[107][176]. Although global hypomethylation is common in primary tumors, it becomes more pronounced in metastatic PCa ^[108][177].  DNMT inhibitors such as azacytidine and decitabine have been developed to target aberrant DNA hypermethylation; furthermore, their efficacy against PCa has been clinically evaluated (NSC127716). In a phase 1/2 study of azacitidine in combination with docetaxel in mCRPC, a PSA response was observed in 52% (10/19) of patients, with no dose-limiting toxicity reported ^[109][178].

4.2. Histone Methylation

Histones undergo methylation when one, two, or three methyl groups are added from S-adenosylmethionine to the side chains of arginine, lysine, and histidine residues. Histone methylations, such as H3K4me1, H3K9me2, and H3K9me3, are reduced in PCa tissues when compared with their levels in normal prostate tissues ^[110][179]. The increased genomic distribution of H3K27me3 in metastatic PCa can primarily be attributed to the overexpression of EZH2 ^[111][154], a histone methyltransferase. EZH2 plays a pivotal role in promoting lineage plasticity and differentiation changes, which are closely associated with neuroendocrine PCa (NEPC) ^[112][181]. The polycomb group proteins EZH2 and embryonic ectoderm development (EED), another member of the PRC2 complex, are currently under investigation as therapeutic targets ^[113][182]. EED functions as a direct regulator of AR and its downstream genes, working in conjunction with EZH2 in the context of AR-positive PCa ^[114][183]. EZH2 represents a promising target, and several EZH2 inhibitors have been identified in early-stage clinical studies ^[115][184].

4.3. Histone Acetylation

Histone acetylation involves the addition of an acetyl group to the lysine residues of histones, leading to the opening and activation of chromatin. Typically, this process is associated with the activation of transcription, whereas histone deacetylation is often linked to gene silencing ^[116][193]. Super-enhancers, which are clusters of enhancers marked by high H3K27ac levels, play a crucial role as drivers of oncogenic processes in cancer cells ^[117][118][194,195]. The activation of histone acetyltransferases, such as p300 and CREB-binding protein (CBP), is strongly associated with an increase in H3K27ac modification frequency ^[119][196]. Histone deacetylases (HDACs) are enzymes responsible for removing histone acetylation; thus far, several types of HDACs have been identified in humans ^[120][200]. Notably, there are five classes of HDAC inhibitors, including hydroxamic acids, cyclic tetrapeptides, short-chain carboxylic acids, benzamides, and ketoderivatives ^[121][201]. HDAC overexpression has been observed in various malignancies, including PCa ^[122][202]. Notably, the expression of HDAC1 and HDAC2 is positively correlated with higher Gleason scores in PCa, whereas that of HDAC1/2/3 is positively associated with the proliferative marker Ki67 ^[123][203]. 

5. Non-Coding RNAs

5.1. Long Non-Coding RNAs (lncRNAs) and Micro-RNAs (miRNAs)

lncRNAs have been implicated in prostate carcinogenesis. They exert their influence through various mechanisms, including regulation of the AR expression pathway, epithelial–mesenchymal transition, miRNAs, and the PI3K/Akt/mTOR pathway; these processes are governed by PCa gene expression marker 1 (PCGEM1), PlncRNA-1, colon cancer-associated transcript 2 (CCAT2), C-terminal binding protein 1 antisense (CTBP1-AS), growth arrest-specific 5 (GAS5), long intergenic non-protein-coding RNA 1296 (LINC01296), LOC400891, and LOC440040, etc. ^{[124][125][126][127][128][129][130][131][132][133]}[207,208,209,210,211,212,213,214,215,216]. LINC00624 is overexpressed in both PCa tissues and cells and is associated with malignant progression. Furthermore, the relationship between NF-κB and PCa is linked to the expression of LINC00624, as it forms a co-regulatory axis with TEX10, stimulating NF-κB activity. Therefore, LINC00624 is hypothesized to function as an oncogene in PCa progression ^[134][90]. The activation of AKT and NF-κB signaling involves a crucial regulatory protein complex comprising PHLPP, FKBP51, and IKKα. The lncRNA PCAT1 is implicated in the regulation of the PHLPP/FKBP51/IKKα complex, directly binding to FKBP51 and excluding PHLPP from the complex. This regulation by PCAT1 contributes to CRPC progression by activating AKT and NF-κB signals ^[135][91]. Upregulated AR expression is a hallmark of CRPC and may serve as a mechanism facilitating AR signaling in the presence or absence of low endogenous androgen levels. Specific lncRNAs, such as CTBP1-AS and HOTAIR, exhibit upregulation following ADT, signifying their negative regulation by androgens. This upregulation of lncRNAs results in increased AR expression. CTBP1-AS upregulation leads to the downregulation of CTBP1, which negatively modulates AR by inhibiting androgen-mediated demethylation. Interaction with miRNAs is another mechanism by which lncRNAs regulate AR activity. PlncRNA-1 likely protects AR from miRNA-mediated suppression ^[128][211] by acting as a sponge for certain AR-targeting miRNAs, including miR-34c and miR-297. PCGEM1 and HOTAIR are reportedly targeted by miR-34a ^[136][219] and miR-145 ^[127][210], respectively. In PCa, both miR-145-5p (the guide strand) and miR-145-3p (the passenger strand) are downregulated. The introduction of these microRNAs into PCa cells reportedly suppresses their proliferative, migratory, and invasive capabilities. The cancer-suppressive functionality of both guide and passenger strands of several microRNAs, including miR-30a, miR-139, miR-143, and miR-145, has been established through large-scale cohort analysis using The Cancer Genome Atlas ^[137][221]. The miRNA expression profile of PCa using needle biopsy samples from CSPC and normal prostate tissues revealed that miR-222 and miR-31 exhibit cancer-suppressive functions ^[138][222]. miR-130b exhibits significant downregulation among miRNAs in PCa tissues, and its expression is significantly reduced in PCa cell lines as well. The decreased expression of miR-130b significantly promotes the proliferation, invasion, and tubule formation of PCa cells, whereas its overexpression suppresses angiogenesis in PCa. miR-130b directly regulates TNF-α, inhibiting the NF-κB signaling pathway and its downstream gene, VEGFA. Furthermore, VEGFA, by reducing the expression of miR-130b, contributes to a feedback loop involving miR-130b/TNF-α/NF-κB/VEGFA that is associated with angiogenesis in PCa ^[139][89]. In PCa, reports of liquid biopsy using upregulated or downregulated microRNAs in the blood (serum, plasma, exosomes) and urine as indicators have been increasing ^[140][224] ^[141][225]. Several studies suggest the detection of cell-free microRNAs, such as miR-141, miR-375, miR-107, and miR-221, in the blood as useful biomarkers for PCa ^[142][226]. Combining miR-17-3p and miR-1185-2-3p for PCa diagnosis has exhibited >90% sensitivity and specificity, highlighting its promise in clinical applications and circumventing the need for unnecessary prostate biopsies ^[143][227].

5.2. Role of miRNAs in PCa Drug Resistance

Growing evidence suggests that miRNAs play a pivotal role in anti-AR drug resistance. For example, miR-23b and miR-27b sensitize CRPC cells to flutamide by targeting CCNG1 ^[144][228]. miR-221 and miR-222, upregulated in CRPC cells, maintain resistance in PCa ^[145][229], and miR-663 affects castration resistance by modulating the AR signal ^[146][230]. In mCRPC, patients with higher levels of miR-375 and miR-3687 in whole blood exhibit a shorter time to progression with enzalutamide treatment ^[147][231]. Additionally, miRNAs play a key role in taxane resistance. Several miRNAs, including miR-34b-3p, miR-199a, miR-200b-3p, and miR-375, have been implicated in paclitaxel resistance ^[148][149][235,236]. Docetaxel resistance is associated with miR-375 and miR-323 upregulation, whereas miR-195, miR-204, miR-143, and miR-200b can enhance docetaxel sensitivity in PCa ^{[150][151][152][153]}[237,238,239,240]. 

6. Prostate-Specific Membrane Antigen (PSMA)

PSMA is a type II transmembrane protein expressed in most high-grade, metastatic, androgen-insensitive, clinically significant cases of PCa. More than 90% of PCa cases exhibit PSMA overexpression at levels reported to be 100–1000 times higher than those in normal prostate tissue ^{[154][155][156][157][158]}[247,248,249,250,251]; however, PSMA is scarcely expressed in benign or hyperplastic prostate tissue ^[159][252]. The organs reported to exhibit high PSMA expression, apart from the prostate, are the kidney, bladder, salivary glands, ganglion, liver, spleen, duodenum, and colon ^{[160][161][162]}[253,254,255]. PSMA is a favorable target for molecular imaging ^{[163][164][165][166][167][168][169]}[256,257,258,259,260,261,262] and therapy ^{[170][171][172][173][174]}[263,264,265,266,267] in PCa. The US Food and Drug Administration (US FDA) has approved three types of radionuclides for positron emission tomography (PET) imaging of PSMA, namely F-18 piflufolastat PSMA, Ga-68 PSMA-11, and F-18 flotufolastat PSMA, for patients with PCa. PSMA PET-computed tomography (PET/CT) or magnetic resonance imaging (PET/MRI) are recommended for detecting metastases and restaging PCa in cases of biochemical recurrence ^[175][268]. In the Advanced Prostate Cancer Consensus Conference (APCCC 2022), 77% of panelists reached a consensus to perform PSMA PET/CT on the majority of patients with clinically localized high-risk PCa. However, 92% of panelists voted not to recommend PSMA PET/CT or MRI for patients with clinically localized favorable intermediate-risk (NCCN definition) PCa ^[176][269]. Determining superiority between ⁶⁸Ga and ¹⁸F-PSMA PET/CT is challenging because their accumulation in normal organs is similar and their diagnostic accuracy does not differ significantly ^{[167][168][169][177]}[260,261,262,270]. Radiation therapy utilizing the labeling of PSMA ligands to target PSMA-positive cells and the surrounding microenvironment involves both alpha and beta radionuclides such as ²²⁵Ac-PSMA and ¹⁷⁷Lu-PSMA, respectively ^{[162][178][179][180]}[255,271,272,273]. 

7. Precision Medicine: Genome-Based Therapy

7.1. PARP Inhibitors (PARPis) for mCRPC with Alterations in HRR Genes

PARP recognizes single-strand DNA breaks and facilitates the transportation of base-excision repair proteins for genetic repair. Conversely, several proteins, including BRCA, play a pivotal role in HRR, particularly in the repair of double-strand DNA breaks. DNA repair can still occur in cases where a malfunction occurs in either PARP or BRCA. However, the administration of PARPis prevents DNA repair in cases where cancer cells exhibit BRCA abnormalities ^{[75][181][182][183][184]}[96,275,276,277,278]. PARPis traps PARP-1 on damaged DNA, inhibiting auto-poly(ADP-ribosyl)ation and enhancing DNA affinity for the catalytic site, ultimately leading to cell death ^{[75][185][186][187]}[96,279,280,281]. PARPis, which were approved by the US FDA in 2023 and are used for monotherapy or combination therapy with other drugs for mCRPC, belong to four types: olaparib, niraparib, rucaparib, and talazoparib. Veliparib is currently undergoing clinical trials ^[188][189][287,288]. Preclinical studies have indicated variations in the ability of PARPi to trap PARP enzymes across different tumor cells, including PCa cells, with talazoparib exhibiting the highest PARP-trapping capacity among the tested inhibitors, followed by niraparib, olaparib, and rucaparib ^[190][289]. 

7.2. Akt Inhibitor for mCRPC with PTEN Deficiency

PTEN typically exerts tumor-suppressor effects by inhibiting the PI3K/Akt/mTOR signaling pathway. However, PTEN deficiency is present in approximately 50% of patients with mCRPC. Upon PTEN protein deficiency, signal transduction through PI3K and Akt occurs via genomic or non-genomic pathways, leading to the dysregulation of the cell cycle and cell proliferation, the enhancement of metabolic pathways such as those for glycolysis and protein translation, and the promotion of vascular neogenesis and cell survival pathways. These processes ultimately culminate in tumor formation and growth ^[191][299]. Ipataseltib is a novel, cooperative, and selective ATP-competitive small-molecule inhibitor targeting all three isoforms of Akt ^[192][301]. A phase 3 trial (IPATentia150 trial: NCT03072238) evaluating the combination therapy of ipatasertib and apalutamide revealed that the median rPFS of mCRPC patients with PTEN deficiency was 18.5 months (95% CI: 16.3–2.1 months) in the ipatasertib + apalutamide group and 16.5 months (95% CI: 13.9–17.0 months) in the placebo + apalutamide group. This combination therapy significantly increased rPFS by 23% (HR: 0.77, 95% CI: 0.61–0.98, p = 0.0335) ^[193][194][302,303]. Akt inhibitors are considered potential novel agents representing the precision medicine era for mCRPC, and a phase 3 randomized CAPItello-280 trial (NCT05348577) is underway to evaluate the efficacy and safety of capivasertib and docetaxel administration as compared to that of placebo and docetaxel administration in the treatment of patients with mCRPC ^[195][304].

7.3. Immune Checkpoint Inhibitors (ICIs) for mCRPC

The programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is pivotal in regulating T-cell activity ^{[196][197][198]}[306,307,308]. Several clinical studies have assessed the efficacy of ICIs, including anti-PD-L1 (nivolumab, atezolizumab, durvalumab, and avelumab), anti-PD1 (pembrolizumab and nivolumab), and anti-CTLA4 (ipilimumab) antibodies. Although preliminary studies have indicated limited anticancer activity of ICIs ^[199][200][309,310], patient selection based on deficiencies in MMR genes is considered crucial, as this patient cohort can potentially respond to ICIs. The FDA has approved the use of the anti-PD1 antibody pembrolizumab for treating cancers, including PCa with MMR mutations or MSI ^[201][311]. Strong correlations were reported between immunohistochemical PD-L1 expression and the efficacy of PD-1 blockade in various malignant tumor cohorts. However, within these cohorts, only two patients had CRPC ^[202][312]; their samples revealed negative PD-L1 expression, suggesting the lack of a significant association. High PD-1 expression was observed in infiltrating T lymphocytes, specifically in CD8-positive prostate tissues, suggesting that they may not effectively mount an immune response ^[203][313]. 

8. Conclusions

PCa is characterized by its androgen dependency, with treatment primarily based on androgen signal deprivation. However, the involvement of driver genes in both the initiation and progression of PCa is highly diverse among cases. Precision medicine, which involves understanding individual genetic alterations and proposing tailored treatment strategies, is considered crucial in the context of PCa. The development of treatments based on genetic mutations such as PARPis for HRR gene mutations, AKT inhibitors for patients with genetic mutations in the PI3K/Akt pathway, and ICI for mutations in MMR genes and cases of MSI-high or high-tumor-mutational-burden CSPC and CRPC is anticipated. Monitoring the treatment progress of patients with PCa using liquid biopsy methods such as miRNA in blood or urine is a promising field that could significantly impact routine PCa treatment.