Beyond Docetaxel: Targeting Resistance Pathways in Prostate Cancer Treatment

Abstract

Prostate cancer continues to be the most common cause of cancer-related disease and mortality among men worldwide, especially in the advanced stages, notably metastatic castration-resistant prostate cancer (mCRPC), which poses significant treatment challenges. Docetaxel, a widely used chemotherapeutic agent, has long served as the standard treatment, offering survival benefits and mitigation. However, its clinical impact is frequently undermined by the development of chemoresistance, which is a formidable challenge that leads to treatment failure and disease progression. The mechanisms driving docetaxel resistance are diverse and complex, encompassing modifications in androgen receptor signaling, drug efflux transporters, epithelial-mesenchymal transition (EMT), microtubule alterations, apoptotic pathway deregulation, and tumor microenvironmental influences. Recent evidence suggests that extracellular RNAs influence drug responses, further complicating the resistance landscape. This review offers a broad discussion on the mechanisms of resistance and explores novel therapeutic approaches to address them. These include next-generation taxanes, targeted molecular inhibitors, immunotherapies, and combination regimens that can be designed to counteract specific resistance pathways. By broadening our understanding of docetaxel resistance, this review highlights potential strategies to improve therapeutic efficacy and the potential to enhance outcomes in patients with advanced treatment-resistant prostate cancer.

1. Introduction

Prostate cancer is one of the most frequently diagnosed malignancies in men and a significant contributor to cancer-related deaths worldwide [1,2]. While early-stage prostate cancer can often be effectively managed through surgery, radiation, or hormonal therapy, a substantial subset of patients eventually progresses to advanced disease, culminating in metastatic castration-resistant prostate cancer (mCRPC) [3,4]. This transition marks a pivotal and challenging stage in the progression of the disease, where tumors continue to thrive despite the sustained suppression of androgen signaling. The approval of docetaxel in the early 2000s was a milestone in the management of CRPC, offering a meaningful survival advantage and improved symptom control. As the first chemotherapeutic agent to demonstrate such benefits in the management of CRPC, docetaxel quickly became the gold standard for the treatment of advanced prostate cancer [1,5]. However, its success is frequently undermined by the gradual development of drug resistance, which remains a major barrier to long-term disease control. Despite its initial efficacy, the inevitable development of docetaxel resistance has become a critical obstacle in CRPC management [6,7], which has led to disease progression and limited treatment options.

Docetaxel resistance arises from diverse molecular changes and adaptive cellular responses. These include alterations in drug transport and metabolism, dysregulation of apoptosis, reactivation of androgen receptor (AR) signaling, and the emergence of stem-like cancer cells [8]. In addition, the tumor microenvironment has been reported to play a pivotal role, with both stromal and endothelial cells promoting chemoresistance through growth factor modulation and paracrine signaling. For example, interactions involving fibroblast growth factor 2 (FGF2) and the oncogenic transcription factor ERG have been implicated in promoting tumor survival under chemotherapeutic stress [7,9]. The increase in clinical drawbacks associated with docetaxel resistance has sparked a surge in the search for potentially effective alternatives. These include the development of alternative novel chemotherapeutic agents, next-generation hormonal agents, immunotherapies, and molecular inhibitors, many of which specifically target different resistance pathways. Moreover, there is a growing interest in the combination of regimens and precision medicine approaches that aim to tailor therapy based on the molecular profile of individual tumors. Combination treatment strategies are gaining attention in the management of advanced prostate cancer for their potential to overcome therapeutic resistance and enhance clinical outcomes. In the CHAARTED and STAMPEDE trials, docetaxel combined with androgen deprivation therapy (ADT) improved overall survival in hormone-sensitive patients, while ongoing investigations are evaluating the optimal sequencing and co-administration of AR inhibitors and taxanes in mCRPC patients [10]. These combinations exploit non-overlapping mechanisms of action and are increasingly being integrated into treatment algorithms.

In this review, the complex mechanisms driving resistance to docetaxel in CRPC were explored and the therapeutic strategies developed to overcome these barriers were examined. By elucidating both the already well-known and emerging pathways of resistance, this review aims to offer a comprehensive overview of the challenges and opportunities in managing chemotherapy-resistant prostate cancer and highlight promising directions for future clinical translation.

2. Mechanisms of Docetaxel Resistance

Docetaxel resistance in prostate cancer arises from a multifaceted network of molecular and cellular alterations. These resistance mechanisms span drug efflux, changes in apoptotic signaling, microtubule dynamics, epithelial-mesenchymal transition (EMT), and influences from the tumor microenvironment. Figure 1 provides an overview of the key pathways implicated in mediating resistance to docetaxel in prostate cancer, highlighting potential targets for therapeutic intervention.

2.1. Drug Efflux and Transporters

Drug efflux transporters, particularly members of the ATP-binding cassette (ABC) family, are crucial in facilitating resistance to the treatment of cancer and infectious disorders. Prominent proteins, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), facilitate the efflux of several therapeutic drugs from cells, thereby reducing intracellular drug concentrations [11]. This efflux activity reduces therapeutic efficacy and facilitates the emergence of multidrug resistance (MDR), which is a significant barrier in the management of malignancies and chronic infections. In [8], Sekino and Teishima stated that the intracellular concentration of docetaxel is dependent on the ratio of drug influx to efflux pumps; therefore, upregulation of efflux transporter activity or downregulation of influx transporter activity may significantly influence the efficacy of docetaxel.

Drug efflux and transporters play crucial roles in the development of docetaxel resistance in prostate cancer. Overexpression of ABCB1 (P-gp) is a well-established mechanism that contributes to this resistance. ABCB1, an ABC transporter, actively pumps docetaxel out of cancer cells, thereby reducing its intracellular concentration and effectiveness [7,8,12]. Overexpression of ABCB1 has been correlated with poor survival rates in various cancers, including prostate cancer, and accounts for the recurrence of resistance to docetaxel therapy [7].

Interestingly, other multidrug resistance proteins (MRPs) also contribute to docetaxel resistance. These include MRP1 (ABCC1) and BCRP (BCRP/ABCG2), which, like ABCB1, can efflux a broad spectrum of anticancer drugs, including docetaxel [12,13]. Interestingly, these transporters are not only expressed on the cell membrane but also in intracellular compartments, where they sequester drugs away from their cellular targets [14]. This intracellular localization adds another layer of complexity to the resistance mechanism.

The overexpression of ABCB1 and other MRPs presents a significant challenge in docetaxel-based prostate cancer treatment. Understanding these resistance pathways is crucial for the development of effective strategies for overcoming them. Potential approaches include the use of ABC transporter inhibitors, the development of novel drug delivery systems to bypass these transporters, and the design of new chemotherapeutic agents that are poor substrates for these efflux pumps [12,15,16]. As we continue to unravel the intricacies of these resistance mechanisms, we will move closer to more effective treatments for docetaxel-resistant prostate cancer.

Targeting ABCB1 using specific inhibitors or modulating its expression and activity presents both opportunities and challenges. Inhibition of ABCB1 with agents such as elacridar has shown promising results in re-sensitizing taxane-resistant prostate cancer cells to treatment. Notably, this strategy can enhance the effectiveness of cabazitaxel in cells that exhibit cross-resistance to both docetaxel and cabazitaxel owing to increased ABCB1 expression [17,18].

The potential success of using ABCB1 inhibitors lies in their ability to restore drug sensitivity and improve treatment outcomes in patients who have developed resistance to taxanes. These inhibitors can be particularly beneficial when combined with antiandrogens, as they have been shown to enhance treatment efficacy and effectively reverse ABCB1-mediated resistance [17]. However, challenges are associated with targeting ABCB1. The broad substrate specificity of P-glycoprotein means that inhibitors can impact the pharmacokinetics of various drugs, leading to potential adverse drug interactions. Additionally, the activation of other resistance mechanisms, such as the upregulation of additional genes within the ABCB1 gene locus, can also contribute to treatment challenges [19]. Overall, while inhibitors of ABCB1 present a viable strategy to combat taxane resistance in prostate cancer, their effective use requires careful consideration of potential off-target effects and the development of combination therapies to manage multifaceted resistance mechanisms [20,21].

2.2. Epithelial-Mesenchymal Transition (EMT)

EMT is a critical biological mechanism by which epithelial cells shed their cell-cell adhesion and adopt a mesenchymal phenotype [22]. This transformation provides cancer cells with several aggressive properties, which are characterized by enhanced invasiveness, the ability to resist therapy, and properties similar to cancer stem cells. As cancer cells undergo EMT, they develop resistance to treatment via mechanisms such as an increase in efflux pumps and evasion of apoptosis, through which they metastasize to distant sites. These changes make EMT a key player in both metastasis and resistance to therapy, highlighting its importance in cancer progression [23].

EMT plays a crucial role in the development of docetaxel resistance in prostate cancer [24]. This process involves a complex interplay of molecular mechanisms that leads to phenotypic changes in cancer cells, enhancing their survival and invasive capabilities. EMT-associated transcription factors, particularly Snail, Twist, and ZEB1, are the key drivers of this transition. These factors facilitate comprehensive cancer cell reprogramming, which promotes the loss of epithelial properties and acquisition of mesenchymal traits [25].

Snail is particularly well-known for its repression of E-cadherin, a key protein responsible for maintaining epithelial integrity [26]. By downregulating E-cadherin, Snail weakens cell-cell adhesion, enabling cancer cells to detach from the primary tumor and migrate, which is an early and critical step in metastasis [26,27]. Elevated Snail expression has been linked to increased invasiveness and poor clinical outcomes in prostate cancer [27]. Twist, another master regulator of EMT, contributes to chemoresistance by promoting cytoskeletal remodeling and activating survival pathways that protect cells under therapeutic stress [28]. Through the induction of mesenchymal traits, Twist enhances the invasive potential of prostate cancer cells, which may allow them to evade docetaxel-induced apoptosis and colonize distant tissues [29,30]. The dual role of Twist in survival and dissemination makes it a potent driver of disease progression. ZEB1 also plays a pivotal role in EMT by repressing epithelial markers and promoting the mesenchymal phenotype [31]. In addition to facilitating invasion and motility, ZEB1 has been associated with the acquisition of stem cell-like properties, which are often linked to drug resistance and tumor relapse [31]. ZEB1 expression correlates with aggressive disease and therapeutic failure in prostate cancer, highlighting its relevance as a potential target for intervention [32]. In docetaxel-resistant prostate cancer, ZEB1 has been identified as a critical player through transcriptional repression of E-cadherin. ZEB1 not only drives EMT, but also contributes significantly to docetaxel resistance [32]. This finding underscores the intricate link between EMT and drug resistance in prostate cancer.

Phenotypic plasticity associated with EMT is particularly noteworthy in the context of docetaxel resistance. As cancer cells undergo EMT, they exhibit increased invasiveness and acquire stem-cell-like properties [33]. This plasticity allows prostate cancer cells to adapt to various microenvironmental stresses including chemotherapy. The transition from a rigid epithelial state to a more flexible mesenchymal phenotype enables these cells to evade the cytotoxic effects of docetaxel and other therapies [34]. Interestingly, the EMT process in prostate cancer is not uniform across all cell types. Studies have revealed differential EMT characteristics in various prostate cancer cell lines, highlighting the heterogeneity of the disease [32]. This variability in EMT manifestations adds another layer of complexity to the clinical management of docetaxel-resistant prostate cancer. In conclusion, EMT is a critical mechanism in docetaxel resistance, driven by specific transcription factors, resulting in enhanced phenotypic plasticity and invasiveness. Understanding these processes opens new avenues for therapeutic intervention, potentially leading to more effective treatments for patients with advanced prostate cancer.

While EMT has been extensively documented in in vitro and in vivo models, its full realization in human prostate tumors remains controversial. Clinical samples often display partial EMT or ‘hybrid’ states, characterized by the co-expression of epithelial (e.g., E-cadherin) and mesenchymal (e.g., vimentin, ZEB1) markers. This phenotypic plasticity may allow tumor cells to retain both adhesive and migratory capacities, facilitating their collective invasion and resistance. However, the clinical evidence for EMT is largely indirect, and functional validation in human tumors remains an area of active research.

2.3. Altered Apoptotic Signaling

Altered apoptotic signaling plays a crucial role in the development of docetaxel resistance in prostate cancer. Two key aspects of this altered signaling involve the dysregulation of Bcl-2 family proteins and abnormalities in p53 and its downstream pathways [35,36]. Bcl-2 family dysregulation is a common feature of docetaxel-resistant prostate cancer cells. The delicate balance between pro-apoptotic and anti-apoptotic Bcl-2 family members is often disrupted, which favors cell survival [35,37]. Upregulation of anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, has been observed in resistant cells [37,38]. These proteins inhibit mitochondrial outer membrane permeabilization (MOMP), which effectively prevents cytochrome c release and downstream activation of caspases, which are key executioners of apoptosis [39]. In contrast, pro-apoptotic proteins such as Bax may be downregulated [37,38]. This shift in balance effectively increases the apoptotic threshold, making cancer cells less susceptible to docetaxel-induced cell death. Interestingly, silencing Notch-1 has been shown to alter this balance by downregulating Bcl-2 and upregulating Bax, potentially re-sensitizing cells to docetaxel [38].

p53 mutations and downstream signaling abnormalities also contribute significantly to docetaxel resistance. As a key tumor suppressor, p53 plays a critical role in initiating apoptosis in response to cellular stress and DNA damage. However, mutations in p53 are common in advanced prostate cancer, leading to impaired apoptotic signaling [37,40]. These mutations can result in the loss of p53 pro-apoptotic function or even gain-of-function effects that promote survival. Moreover, alterations in p53 downstream effectors can further compromise the apoptotic response, even in cases where p53 itself remains wild type [41]. In clinical settings, alterations in the tumor suppressor genes TP53 and RB1 are frequently observed in docetaxel-resistant prostate cancer and are strongly associated with poor therapeutic response and aggressive disease phenotypes [42]. These genomic disruptions compromise key regulatory checkpoints governing apoptosis and cell cycle progression, thereby facilitating resistance to taxane-based therapies. Additionally, ERG gene rearrangements, particularly the TMPRSS2-ERG fusion, have been implicated in taxane resistance by modifying microtubule dynamics and disrupting drug–target interactions. Notably, the prevalence of TMPRSS2-ERG fusions exhibits distinct racial disparities, being most common in men of European descent (approximately 49%), followed by those of Asian (27%) and African ancestry (25%) [43]. This variation suggests that population-specific molecular drivers may underlie prostate cancer progression and therapeutic resistance, underscoring the importance of personalized treatment approaches and further research into ethnicity-informed genomic mechanisms.

The interplay between these altered apoptotic pathways creates a barrier to effective docetaxel treatment. However, understanding these mechanisms opens new avenues for therapeutic interventions. Targeting Bcl-2 family proteins, for instance, has shown promise for overcoming resistance. Venetoclax, a selective Bcl-2 inhibitor, has demonstrated potent pro-apoptotic effects in hematologic malignancies and shows promise as a treatment for prostate cancer, particularly in mCRPC [44]. Preclinical studies as part of combination regimens suggest that it may enhance sensitivity to taxanes and other agents by lowering the apoptotic threshold [45]. However, venetoclax is not yet approved for use in mCRPC, and clinical trials evaluating its efficacy in this setting are limited or ongoing. Therefore, while targeting the Bcl-2 axis represents a promising therapeutic avenue, further validation is required to establish its clinical utility in patients with mCRPC.

Similarly, strategies to restore p53 function or target its downstream pathways are being actively explored as potential means to re-sensitize resistant cells to docetaxel [40]. In summary, altered apoptotic signaling, particularly through Bcl-2 family dysregulation and p53 abnormalities, represents a critical mechanism of docetaxel resistance in prostate cancer. Addressing these alterations may be key to developing more effective treatment strategies for patients with resistant diseases.

2.4. Microtubule Alterations

One of the most clinically relevant mechanisms by which prostate cancer cells evade the cytotoxic effects of docetaxel involves subtle yet impactful changes to the primary drug target, the microtubules. Docetaxel functions by binding to β-tubulin subunits in microtubules, stabilizing these structures, and freezing the cell during mitosis. Prolonged mitotic arrest typically triggers apoptosis [46]. However, as with many therapeutic strategies in oncology, tumor cells often find ways to adapt. Two interrelated changes, β-tubulin mutations and isotype switching, are central to resistance. Mutations in the β-tubulin gene can alter the drug-binding interface, reducing the affinity of docetaxel for microtubules and diminishing its ability to stabilize these polymers. While these mutations may not be widespread in prostate cancer, their presence can critically impair therapeutic efficacy [46]. Even minor conformational changes in the tubulin structure could be sufficient to permit continued microtubule dynamics and cellular division despite the presence of docetaxel. Although β-tubulin mutations can reduce docetaxel binding affinity in some malignancies, these mutations are considered rare in prostate cancer and have limited clinical relevance [47].

Prostate cancer cells commonly resort to β-tubulin isotype switching as a resistance strategy [46]. Normally, class I and II β-tubulin isoforms are dominant in the epithelial tissues. However, resistant tumors often upregulate class III β-tubulin (TUBB3), a variant typically confined to neuronal tissues. This isoform has a low binding affinity for taxanes and contributes to increased microtubule instability. As a result, TUBB3 expression not only dampens mitotic arrest induced by docetaxel but also enhances cell plasticity, motility, and invasiveness, traits strongly linked to cancer progression and metastasis [8,46]. These microtubule alterations are more than molecular curiosities; they are part of a larger adaptive landscape that allows tumor cells to survive under therapeutic pressure. By weakening the stabilizing effect of docetaxel and enhancing its structural flexibility, such alterations pave the way for treatment resistance, disease persistence, and eventual recurrence [8,46].

Encouragingly, research has begun to identify methods to bypass or counter these resistance mechanisms. New-generation taxanes designed to bind β-tubulin isoforms with higher affinity, including TUBB3, are currently under investigation. Additionally, alternative agents, such as mebendazole, which disrupt microtubules through a distinct mechanism, have shown promise when combined with docetaxel, offering a synergistic approach to overcoming resistance [48]. Understanding how microtubule composition and dynamics shift under drug pressure is essential for advancing personalized therapies for prostate cancer. By targeting these specific resistance pathways, we have opened the door to more durable responses and improved outcomes for patients whose tumors have become refractory to standard taxane therapy.

2.5. Tumor Microenvironment Influence

The tumor microenvironment (TME) plays a crucial role in the development of docetaxel resistance in prostate cancer. Hypoxia and inflammatory cytokines, along with cancer-associated fibroblasts and immune cells, significantly contribute to this resistance mechanism. Hypoxia, a common feature of solid tumors, activates hypoxia-inducible factors (HIFs) that mediate cellular adaptations to low-oxygen conditions [49]. In prostate cancer, HIFs regulate various signaling pathways, including PI3K/Akt/mTOR and Wnt/β-catenin, which promote tumor progression and drug resistance [49]. While the influence of the tumor microenvironment on chemoresistance is well characterized in pancreatic and breast cancers, emerging evidence suggests that similar processes may contribute to therapy resistance in prostate cancer, although direct experimental validation remains limited. Hypoxia-induced activation of HIF signaling and downstream pro-survival pathways (e.g., PI3K/Akt/mTOR and Wnt/β-catenin) has been observed in prostate tumors [49]. Hypoxia also induces the secretion of inflammatory cytokines such as IL-6 and TNF-α, which further contribute to docetaxel resistance. IL-6, in particular, has been shown to modulate prostate cancer progression and may play a role in treatment resistance [50].

Cancer-associated fibroblasts (CAFs) and immune cells within the tumor microenvironment contribute to docetaxel resistance. CAFs, which are highly sensitive to hypoxia, participate in crosstalk with cancer cells and modulate several mechanisms that induce cancer malignancy, including drug resistance [51]. They secrete factors that can alter the tumor microenvironment and promote cancer cell survival in the presence of chemotherapy. Similarly, immune cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) can be recruited to the tumor site and reprogrammed to support cancer progression and treatment resistance [52,53].

The complex interplay between hypoxia, inflammatory cytokines, CAFs, and immune cells in the tumor microenvironment creates a protective niche for prostate cancer cells, contributing to docetaxel resistance. Understanding these interactions is crucial for developing more effective treatment strategies that target not only cancer cells but also the supporting tumor microenvironment.

In prostate cancer treatment, multifactorial resistance can be attributed to interconnected mechanisms involving EMT, cancer stem cells (CSCs), and immune evasion. EMT is a critical process that contributes to aggressive tumor biology and therapy resistance and plays a pivotal role in the generation and maintenance of CSCs. These CSCs are intrinsically resistant to conventional therapies, chiefly because of their ability to self-renew and undergo multilineage progenitor expansion, leading to tumor recurrence and metastasis [54,55,56].

The TME significantly influences these processes. Components such as TAMs and cancer-associated fibroblasts (CAFs) play crucial roles in fostering an environment that promotes EMT and supports CSC stemness. For instance, TAMs create a pro-thrombotic environment by secreting inflammatory cytokines and chemokines, which support EMT and enhance multidrug resistance (MDR) [57]. Similarly, CAFs are instrumental in modulating the ecological niche of prostate cancer stem cells (PCSCs), which aids in PCSC growth, survival, and stemness, facilitating the resilience of these cells to therapies [58].

Moreover, the interplay between EMT and CSC phenotypes fosters immune evasion, further complicating treatment strategies. As EMT progresses, CSCs exploit immune system alterations to evade immune response. For example, myeloid-derived suppressor cells (MDSCs) and TAMs create an immunosuppressive environment by fostering chronic inflammation, which nurtures CSCs and leads to tumor persistence and resistance. These immune cells facilitate immune evasion by promoting conditions that allow CSCs to avoid immune detection and destruction, thus aiding resistance [59].

Therapeutic resistance pathways in prostate cancer are highly interlinked. The back-and-forth crosstalk between CSCs and the TME, encompassing TAMs and CAFs, facilitates the development of resistance mechanisms. Targeting multiple components of this network holds promise for overcoming these resistance pathways. For example, therapies that inhibit EMT and those targeting CSCs may attenuate stemness and reduce resistance. Additionally, targeting inflammatory processes within the TME using immunomodulatory compounds can potentially reduce MDR, highlighting the need for therapeutic strategies that address these multifaceted interactions [60,61].

3. Emerging Therapies and Combination Strategies

As our understanding of the mechanisms underlying docetaxel resistance in prostate cancer deepens, a growing number of therapeutic strategies are being developed to counteract these challenges. These interventions are designed to target key resistance pathways and restore drug sensitivity, offering renewed hope for treatment-refractory cases. Figure 2 summarizes the major emerging strategies aimed at overcoming docetaxel resistance and highlights the multifaceted nature of these targeted approaches.

Table 1. Approved and investigational therapies for mCRPC, including their mechanisms of action and clinical status.

Agent	Type	Mechanism of Action	Status
Cabazitaxel	Second-gen taxane	Binds β-tubulin, overcomes P-gp-mediated efflux	FDA approved
Enzalutamide	AR antagonist	Inhibits AR nuclear translocation	FDA approved
Abiraterone acetate	CYP17 inhibitor	Blocks androgen biosynthesis	FDA approved
Olaparib	PARP inhibitor	Exploits DNA repair defects (e.g., BRCA mutations)	FDA approved
Ipilimumab + Nivolumab	Immune checkpoint blockade	Targets CTLA-4 and PD-1	Phase III trials
AZD5363 (Capivasertib)	AKT inhibitor	Blocks PI3K/AKT pathway	Phase I trials
AVB-S6-500 batiraxcept	AXL inhibitor	Reverse EMT, decreasing the expression of mesenchymal markers and increasing the expression of epithelial markers like E-cadherin	Phase I/II trials
BET inhibitors (e.g., ZEN-3694)	Epigenetic modulators	Inhibit transcriptional reprogramming	Phase I/II trials
Sipuleucel-T	Therapeutic cancer vaccine	Activation of patient’s immune system to target prostatic acid phosphatase (PAP)	FDA Approved
Radium-223	Radiopharmaceutical	The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumor cells, osteoblasts, and osteoclasts.	FDA Approved
Niraparib (Akeega) combined with abiraterone acetate and prednisone	PARP inhibitor	Exploits DNA repair defects (e.g., BRCA mutations)	FDA approved

summarizes approved and investigational therapies for mCRPC along with their mechanisms of action.

Cabazitaxel, a second-generation taxane, has emerged as a crucial treatment option for patients with mCRPC whose disease has progressed after a docetaxel therapy regimen. Its efficacy was demonstrated in the TROPIC trial, which showed improved overall survival compared to mitoxantrone in docetaxel-pretreated patients [62]. Cabazitaxel’s ability to overcome common resistance mechanisms limiting the efficacy of older taxanes has made it a valuable addition to the prostate cancer treatment arsenal. However, cabazitaxel resistance remains a significant challenge. Recent studies have uncovered several potential resistance mechanisms, including ERG overexpression, which affects microtubule dynamics and inhibits drug-target engagement [9]. However, it is important to note that these findings are largely derived from preclinical models, and the clinical relevance of ERG status as a predictive biomarker for taxane response, particularly for cabazitaxel, remains limited. Further translational studies and prospective clinical trials are needed to evaluate whether ERG expression can reliably inform taxane selection or predict resistance in patients with mCRPC. Additionally, the development of cross-resistance between taxanes and antiandrogen drugs, such as abiraterone and enzalutamide, has been observed, further complicating treatment strategies [63].

Interestingly, the combination of cabazitaxel with androgen receptor (AR)-targeting agents has shown promise in preclinical models. In androgen-responsive tumors, enzalutamide was found to overcome resistance to cabazitaxel, inducing mesenchymal-epithelial transition and multinucleation [64]. However, this combination may not be effective for CRPC, highlighting the need for biomarker-driven treatment approaches. While cabazitaxel remains the primary second-generation taxane in clinical use for prostate cancer, research on other novel taxanes is ongoing. These efforts are aimed at developing compounds with improved efficacy and reduced toxicity profiles. For instance, some studies have explored the potential of combining taxanes with natural compounds, such as fisetin, which has shown synergistic effects with cabazitaxel in preclinical models [65]. Although cabazitaxel has significantly improved outcomes for mCRPC patients with mCRPC, ongoing research is crucial to overcome resistance mechanisms and identify optimal combination strategies. The development of biomarkers such as ERG status or RB loss [66] may help in patient selection for taxane therapy and guide personalized treatment approaches in the future.

3.1. Targeting EMT and Stemness

Targeting EMT and stemness has emerged as a promising approach to combat prostate cancer resistance to docetaxel and other conventional therapies. The interplay between EMT and cancer stem cells (CSCs) contributes significantly to resistance to therapy and disease progression in prostate cancer [32,67]. EMT inhibitors and differentiation therapies offer novel strategies for overcoming these resistance mechanisms. ZEB1, a key transcription factor that drives EMT in prostate cancer, has been identified as a potential target. The inhibition of ZEB1 can reverse EMT and potentially re-sensitize resistant cells to docetaxel [32]. Additionally, targeting the mTOR pathway, which plays a crucial role in regulating CSCs and the EMT, may provide another avenue for intervention. Combining mTOR inhibitors with conventional therapies could potentially eradicate CSCs and improve treatment outcomes [68].

Interestingly, androgen deprivation therapy (ADT), which was initially effective, has been shown to activate EMT and neuroendocrine transdifferentiation in prostate cancer cells. This paradoxical effect highlights the complexity of targeting these pathways and emphasizes the need for carefully designed combination strategies [67]. Emerging therapies targeting the molecular drivers of EMT and stemness, such as Brachyury, Axl, MEK, and Aurora kinase A inhibitors, are currently being evaluated in clinical trials and may offer new hope for patients with resistant disease [67,69]. Targeting EMT and stemness represents a promising approach for overcoming resistance to prostate cancer treatment. However, the heterogeneity of prostate cancer and the complex interplay between various signaling pathways necessitate a multifaceted approach. Future research should focus on developing personalized combination therapies that effectively target both differentiated tumor cells and CSCs while considering the unique molecular profile of each tumor [70]. Therapeutic targeting of EMT has garnered attention because of its role in promoting drug resistance and metastasis. While numerous small molecules and biologics have shown promise in preclinical models by targeting key EMT regulators (e.g., TGF-β inhibitors, Wnt pathway modulators, and Notch inhibitors), it is important to note that no EMT-specific inhibitors are currently approved for mCRPC. Clinical translation remains limited, and ongoing trials are primarily focused on combining EMT pathway inhibition with chemotherapy or immunotherapy to enhance treatment response.

3.2. Inhibition of Drug Efflux Pumps

In the ongoing battle against prostate cancer resistance, the inhibition of drug efflux pumps, particularly P-gp, has emerged as a promising strategy to enhance the efficacy of chemotherapeutic agents such as docetaxel. P-gp, encoded by MDR1, is an ABC transporter that actively pumps various anticancer drugs out of cancer cells and contributes to MDR [11,71]. Several generations of P-gp inhibitors have been developed and tested in clinical trials. First-generation inhibitors, such as verapamil and cyclosporine A, which show promise in vitro, face limitations due to their lack of specificity and high toxicity at the doses required for P-gp inhibition. Second-generation inhibitors, such as valspodar, aim to address these issues, but still encounter pharmacokinetic interactions with anticancer drugs [71]. The field then progressed to third-generation inhibitors including biricodar, zosuquidar, and laniquidar, which were specifically designed for MDR reversal and showed improved potency and selectivity [71,72].

Despite these advancements, clinical trials of P-gp inhibitors have yielded disappointing results. The reasons for this are multifaceted, including poor trial design, inadequate patient selection, and an incomplete understanding of the complex nature of drug resistance in prostate cancer [72]. However, it is worth noting that a few randomized trials have shown statistically significant benefits when P-gp inhibitors are combined with chemotherapy, offering a glimmer of hope for this approach [11]. The recent availability of high-resolution structural information for P-gp has opened new avenues for the rational, structure-based design of more potent and specific inhibitors [72]. These next-generation inhibitors may prove more effective in overcoming P-gp-mediated resistance when combined with chemotherapeutics, such as docetaxel, in carefully selected patients with prostate cancer. Additionally, there is a growing interest in using P-gp inhibitors to increase the oral bioavailability and brain penetration of anticancer drugs, which could be particularly relevant for treating metastatic prostate cancer [72].

As we continue to unravel the complexities of drug resistance in prostate cancer, it is becoming clear that a one-size-fits-all approach is unlikely to be successful. The future of P-gp inhibition in prostate cancer treatment lies in personalized strategies that consider the specific resistance mechanisms at play in individual patients and at different stages of the disease [73]. By combining P-gp inhibitors with other targeted therapies and employing biomarker-driven patient selection, we may realize the full potential of this approach to overcome docetaxel resistance and improve outcomes for prostate cancer patients.

3.3. Epigenetic Modulators

Epigenetic modulators, particularly HDAC and DNMT inhibitors, have emerged as promising sensitizers for prostate cancer treatment, offering the potential to overcome resistance mechanisms and enhance the efficacy of existing therapies. HDAC inhibitors have shown promise in preclinical studies, demonstrating their ability to modulate gene expression and cellular processes in prostate cancer cells. However, their clinical performance as single agents has been disappointing, with phase II trials of vorinostat, pracinostat, panobinostat, and romidepsin failing to progress to phase III owing to toxicity and disease progression issues [74]. This setback highlights the complexity of HDAC biology in prostate cancer and underscores the need for a more nuanced approach to their application.

The lack of progress in HDAC inhibitors beyond Phase II is attributed to the significant toxicity and limited efficacy of overexpressing HDACs in castration-resistant prostate cancer (CRPC) [74]. Insights suggest that a more extensive characterization of HDACs within prostate tumors may aid in designing more subtype-specific inhibitors that could improve clinical outcomes [74]. Similarly, DNMT inhibitors, such as 5-azacytidine and decitabine, have demonstrated some efficacy in hematologic malignancies but are less effective in solid tumors, including prostate cancer. Their lack of specificity and substantial toxicity, coupled with poor bioavailability, are major hurdles in their use [75]. These inhibitors re-activate tumor suppressor genes silenced by methylation but lack the robust and specific action required for effective treatment of solid tumors [76].

Interestingly, the combination of HDAC inhibitors with other therapeutic agents may hold the key to unlocking their potential. For instance, pairing HDAC inhibitors with immunotherapy has shown promise in enhancing immune responses against tumors [77]. This synergistic effect could be particularly valuable in prostate cancer, in which immune evasion is a significant challenge. On the other hand, DNMT inhibitors have demonstrated the ability to reverse aberrant DNA methylation patterns in cancer cells, potentially reactivating silenced tumor suppressor genes [78,79]. Although their efficacy as single agents in solid tumors has been limited, recent studies suggest that using lower doses of DNMT inhibitors in combination with other therapies, such as HDAC inhibitors, may yield better results [80]. The rationale for combining DNMT inhibitors with cytotoxic agents such as docetaxel is compelling. By altering the DNA-protein complex, DNMT inhibitors can potentially enhance the accessibility and efficacy of cytotoxic drugs [79]. This approach could be particularly relevant in overcoming docetaxel resistance in prostate cancer.

However, it is crucial to note that epigenetic modulation is a double-edged sword. Although it offers the potential to reverse harmful epigenetic changes, it may also have unintended consequences on gene expression [80]. As we continue to explore these therapies, we must remain vigilant about their potential long-term effects and strive to develop more targeted approaches. In conclusion, while HDAC and DNMT inhibitors have faced challenges as monotherapies for prostate cancer, their potential as sensitizers in combination strategies is promising. Future research should focus on optimizing dosing regimens, identifying synergistic combinations, and developing biomarkers to predict treatment responses. As we continue to unravel the complex epigenetic landscape of prostate cancer, these modulators may play crucial roles in overcoming treatment resistance and improving patient outcomes.

3.4. Immunotherapy and Immune Modulation

Immune checkpoint inhibitors have emerged as promising avenues for prostate cancer treatment, offering a novel approach to overcome resistance mechanisms. These agents, particularly those targeting PD-1/PD-L1 and CTLA-4 pathways, have shown remarkable success in various cancer types [81]. However, their efficacy in prostate cancer is limited when used as monotherapy [82]. This challenge has led researchers to explore combination strategies to enhance the effectiveness of immune checkpoint blockades in prostate cancer. Interestingly, the combination of immune checkpoint inhibitors with traditional chemotherapy, such as docetaxel, has shown potential synergistic effects. This approach aims to leverage immunogenic cell death induced by chemotherapy to enhance the efficacy of immunotherapy [83]. The rationale behind this combination is that chemotherapy-induced tumor cell death can release tumor-specific antigens, making the cancer more visible to the immune system, and potentially increasing the effectiveness of checkpoint inhibitors.

Although immune checkpoint inhibitors alone have shown limited success in prostate cancer, their combination with chemotherapy represents a promising strategy for overcoming resistance. This approach harnesses the strengths of both modalities: the direct cytotoxic effects of chemotherapy and the immune-activating properties of checkpoint inhibitors. Ongoing clinical trials are exploring various combinations to optimize this approach, with the ultimate goal of improving outcomes in patients with resistant prostate cancer [82,84]. As we continue to unravel the complex interplay between the immune system and cancer cells, these combination strategies may pave the way for more effective and durable responses to prostate cancer treatment.

Recent clinical trials, including KEYNOTE-199, have highlighted the limited efficacy of PD-1/PD-L1 inhibitors in treating unselected patients with metastatic castration-resistant prostate cancer (mCRPC). The KEYNOTE-199 trial specifically investigated the use of pembrolizumab, a PD-1 inhibitor, in patients with mCRPC [85]. The results showed modest antitumor activity, with a response observed in a minority of patients, indicating limited overall efficacy in an unselected mCRPC population [85].

The limited effectiveness of PD-1/PD-L1 inhibitors in mCRPC is partly attributed to the unique characteristics of the tumor microenvironment of prostate cancer. Prostate tumors are often described as “cold” tumors because of their low levels of infiltrating immune cells and low tumor mutational burden (TMB). These factors contribute to an immunosuppressive microenvironment that is not conducive to the success of immune checkpoint inhibitors, which rely on reinvigorating immune responses against tumors. A higher mutational burden generally correlates with a greater number of neoantigens, making tumors more recognizable to the immune cells. However, the low TMB in prostate cancer means fewer targets for the immune system, thus reducing the potential effectiveness of immunotherapy [86].

However, translating these findings into clinical practice involves several challenges. Therefore, understanding which subgroups of patients might benefit from PD-1/PD-L1 inhibitors is crucial. Current research indicates that patients with high PD-L1 tumor expression, increased TMB, or specific genetic alterations, such as microsatellite instability or mismatch repair deficiencies, may have better responses to these therapies. Thus, identifying predictive biomarkers is essential for selecting appropriate patients and improving treatment outcomes [86]. Overall, while PD-1/PD-L1 inhibitors have shown unprecedented success in various cancers, their limited efficacy in unselected mCRPC populations necessitates a deeper understanding of the prostate cancer immune microenvironment and a more personalized approach to treatment.

3.5. Targeted Therapies

In the realm of targeted therapies for prostate cancer, PARP inhibitors have emerged as a promising approach, particularly for tumors with DNA repair deficiencies. These inhibitors exploit synthetic lethality in cancer cells harboring mutations in DNA repair genes such as BRCA1/2, ATM, and PALB2 [87]. Clinical trials have demonstrated the efficacy of PARP inhibitors such as olaparib and rucaparib in patients with mCRPC with these genetic alterations, leading to their FDA approval [88].

Despite their clinical utility in mCRPC patients with BRCA1/2 or other HRR gene mutations, resistance to PARP inhibitors frequently occurs. One of the best-documented mechanisms involves reversion mutations in BRCA2, which restore the open reading frame and functional HR repair capacity, thereby diminishing the synthetic lethality induced by PARP inhibition [89]. These reversion events have been observed in tumor biopsies and circulating tumor DNA from patients progressing to PARP inhibitors. Additional resistance mechanisms include the loss of 53BP1, which enables DNA end resection and compensatory HR activity, as well as the upregulation of efflux transporters, such as ABCB1, which can reduce intracellular PARPi concentrations [90]. Understanding these resistance pathways is crucial for optimizing PARP inhibitor use and guiding combination therapy development.

Interestingly, combining PARP inhibitors with androgen receptor (AR) signaling inhibitors, such as enzalutamide or abiraterone, has shown synergistic effects in preclinical models and early-phase clinical trials [91]. This synergy is thought to arise from crosstalk between AR signaling and DNA repair pathways, where AR inhibition can induce a “BRCAness” phenotype, sensitizing cells to PARP inhibition [92]. However, it is crucial to note that while these combinations show promise, they may also increase the risk of toxicity, necessitating careful patient selection and monitoring [93].

Over the years, prostate cancer treatment has transitioned from a one-size-fits-all approach to increasingly personalized strategies. The integration of genomic profiling to guide treatment decisions, particularly for PARP inhibitor use, represents a significant advancement in this field. However, we must remain vigilant about the potential resistance mechanisms that may emerge with these targeted therapies, as we have seen with other cancer types. Identifying biomarkers of response and resistance will be crucial for optimizing these treatment strategies and improving outcomes in patients with advanced prostate cancer.

4. Clinical Implications and Future Directions

The clinical implications of targeting resistance pathways in prostate cancer treatment beyond docetaxel are profound, with significant potential to improve patient outcomes. Biomarker-driven treatment has emerged as a crucial approach in precision oncology, allowing for personalized and effective therapies [94]. By identifying specific molecular alterations in individual patients, clinicians can tailor treatment strategies to target the unique vulnerabilities of each tumor. Stratifying patients based on resistance signatures is becoming increasingly important for prostate cancer management. Recent advances in the genomic profiling of mCRPC have revealed multiple targetable alterations, opening up new avenues for treatment [94]. For instance, patients with DNA repair pathway alterations may benefit from PARP-1 inhibition, highlighting the potential of genomically stratified targeted therapies.

Integrating omics and precision medicine approaches has revolutionized prostate cancer research and treatment. Multi-omics studies, including genomics, proteomics, and metabolomics, provide a comprehensive understanding of tumor biology and resistance mechanisms [95]. This integrative approach not only aids in biomarker discovery but also in identifying novel therapeutic targets and predicting treatment responses [96]. However, it is crucial to address racial disparities and to ensure equitable access to advanced therapies. While the mechanisms of resistance are well-studied, precise prevalence figures for specific resistance-conferring mutations in broader clinical settings are less commonly reported. Studies often focus on identifying potential resistance mechanisms rather than on the frequency of specific mutations within a patient population. Another study found no significant difference in clinical outcomes by race (White, Black, and Asian) in men with mCRPC treated with docetaxel and prednisone [97]. However, racial disparities in the incidence and mortality of prostate cancer are known to exist. Other studies have shown a lower risk of death in Black men than in White men with mCRPC treated with docetaxel and prednisone [97]. This suggests that racial differences may exist in response to treatment, potentially due to variations in underlying biology, social factors, or a combination of both factors [97].

While precision medicine holds great promise, we must be mindful of potential disparities in access to genomic testing and targeted therapies. Efforts should be made to include diverse populations in clinical trials and to ensure that the benefits of precision oncology reach all patient groups. As we move forward, the integration of liquid biopsy techniques, such as profiling circulating tumor cells or cell-free tumor DNA, shows promise for the real-time monitoring of treatment response and resistance development [94]. This noninvasive approach could enable more dynamic and personalized treatment strategies, potentially improving outcomes for patients with advanced prostate cancer.

5. Conclusions

The treatment landscape for advanced prostate cancer has evolved significantly; however, resistance to therapy remains a critical challenge. Multiple mechanisms contribute to the development of CRPC and resistance to docetaxel, including aberrant AR signaling, EMT, and overexpression of drug efflux pumps, such as ABCB1 [98,99]. These resistance pathways often work in concert, creating a complex and adaptive tumor microenvironment that evades current treatment strategies [33].

Despite these challenges, recent advances have promised to overcome this resistance. Novel combinations of AR-targeted therapies such as enzalutamide and abiraterone with chemotherapy or immunotherapy have shown potential in clinical trials. In addition, dual-targeting strategies, particularly the simultaneous inhibition of androgen receptors (AR) and DNA repair pathways, offer a promising approach to overcoming drug resistance. LX1, for example, targets both AR variants and steroidogenic enzymes, showing potential to combat resistance and enhance the efficacy of standard therapies [100]. Additionally, targeting specific molecular pathways, such as AXL inhibition in docetaxel-resistant prostate cancer, has demonstrated synergistic effects when combined with conventional treatment [98]. The emergence of precision oncology approaches, including genomic testing and liquid biopsies, may further improve patient selection for targeted therapies and clinical trials. The integration of liquid biopsies, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), represents a transformative approach for the real-time tracking of therapy resistance. These methodologies allow for noninvasive, longitudinal assessment of tumor dynamics and resistance mechanisms, thereby aiding in the personalization of treatment strategies [101]. The ability of liquid biopsies to reflect the heterogeneous nature of prostate cancer enhances our understanding of disease progression and therapeutic response, which is crucial for guiding effective precision medicine. Continuous translational research remains crucial for addressing the evolving nature of prostate cancer resistance. Future efforts should focus on elucidating optimal treatment sequences, identifying predictive biomarkers, and developing novel agents that target emerging resistance mechanisms. By bridging the gap between laboratory discoveries and clinical applications, we hope to improve outcomes in patients with resistant prostate cancer and potentially transform this lethal disease into a manageable chronic condition.

Moreover, addressing racial disparities is a crucial research priority. Research indicates significant disparities in prostate cancer outcomes among racial and ethnic minorities. African American men, for instance, experience higher rates of prostate cancer incidence and mortality, often due to a combination of socioeconomic factors, limited access to health care, and genetic variations influencing disease prevalence and response to treatment [102,103]. Ensuring diverse representation in clinical trials and understanding the molecular underpinnings of these disparities are imperative for formulating effective interventions and reducing mortality [102,104].