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Decoding Prostate Cancer: Drug Resistance And Precision Medicine (Part II)

22 September 2025

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Last week, we presented an overview of prostate cancer development, targeted therapeutic strategies, and the core molecular mechanism—the androgen receptor (AR) signalling pathway. This installment explores the mechanisms of drug resistance in prostate cancer and targeted treatment strategies for bone metastasis.

Mechanisms of Drug Resistance in Prostate Cancer

· Resistance to Chemotherapeutic Agents:

Microtubule-targeting drugs like Cabazitaxel and Docetaxel treat prostate cancer by inducing tumour cell apoptosis through their effects on microtubule assembly (NCT01308580). Docetaxel was the first systemic treatment to improve overall survival when combined with androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer (mCSPC) [1]. These drugs also effectively inhibit androgen receptor (AR) nuclear translocation, which depends on cytoskeletal integrity. However, resistance development limits their clinical effectiveness.

Resistance occurs through several mechanisms. Prostate cancer cells frequently overexpress surface glycoproteins such as P-gp (including MDR1), which act as efflux pumps that expel chemotherapeutic agents from cells [2]. The MDR1 inhibitor Tariquidar can effectively restore chemotherapy sensitivity. Additionally, tubulin variant mutations in prostate cancer cells reduce the recognition and binding of microtubule-targeting drugs. Furthermore, the ERG-TMPRSS2 fusion gene inhibits the TP53/RB1 pathway, preventing cellular senescence and allowing cells to repair their genomes after microtubule damage, thereby decreasing sensitivity to these drugs.

· Resistance to AR Inhibitors:

As mentioned previously, the AR signalling pathway is fundamental to prostate cancer development. Numerous AR inhibitors have been developed for treatment, including Abiraterone (which blocks androgen synthesis) and Enzalutamide (which blocks androgen receptors). However, many patients develop castration-resistant prostate cancer (CRPC) after ADT, acquiring resistance to androgen deprivation. From a molecular perspective, CRPC arises through multiple mechanisms:

1. Amplification or overexpression of the AR gene, enabling prostate cancer cells to respond to minimal androgen levels

2. As illustrated in Figure 1, prostate cells typically process testosterone from the testes to synthesize the more potent dihydrotestosterone (DHT), or convert dehydroepiandrosterone (DHEA) from the adrenal glands into testosterone or DHT, which stimulates AR-mediated gene expression. However, CRPC can develop mutations that enable autonomous production and secretion of testosterone, activating AR receptors and increasing intraprostatic androgen levels, thereby rendering ADT ineffective.

3. AR receptor mutations are common in CRPC, such as the truncated ARV7 variant, which lacks the ligand-binding domain and can be constitutively activated without androgen stimulation. Point mutations in AR [3] can enable binding to glucocorticoids, facilitating nuclear translocation and gene activation. Some AR mutations can even convert AR inhibitors into agonists [4]. PROTAC degraders targeting AR, such as ARV-110, effectively overcome resistance caused by truncated or point-mutated AR variants.

4. Development of neuroendocrine prostate cancer (NEPC): Prostate cancer exhibits significant cellular heterogeneity and lineage plasticity. Some tumour cells with low AR expression survive ADT or undergo neuroendocrine differentiation, developing into NEPC and causing tumour recurrence after ADT [5]. Research indicates that FOXA1 mutations can induce plasticity in prostate cancer cells, reprogramming them to a progenitor-like state, facilitating NEPC transformation and enhancing AR resistance [6].

Figure 1. Androgen receptor signalling pathway and mechanisms of resistance [8].

· Resistance to PARP Inhibitors:

Poly(ADP-ribose) polymerase (PARP) proteins are responsible for DNA repair and transcriptional regulation, preventing double-strand breaks (DSBs) by repairing single-strand breaks (SSBs). In prostate cancer cells, frequent genetic mutations lead to high rates of genomic damage; inadequate DNA repair triggers apoptosis. PARP inhibitors exploit "synthetic lethality," selectively killing tumour cells with homologous recombination repair (HRR) deficiencies (such as BRCA1/2 mutations): PARP inhibition causes unrepaired SSBs to convert to DSBs, which HRR-deficient cells cannot repair, ultimately leading to apoptosis. One of the most common mechanisms of PARP inhibitor resistance involves secondary mutations that restore HRR functionality, such as frameshift or nonsense mutations in the open reading frames of HRR repair genes [7]. Additionally, protection of DNA replication forks, demethylation of BRCA-1 and RAD51C promoter regions, and BRCA-1 variants all play crucial roles in PARP inhibitor resistance.

Bone Metastasis in Prostate Cancer

Metastasis is a leading cause of death in advanced prostate cancer. After breaching the basement membrane, late-stage prostate cancer can spread to various organs, including the liver, lymph nodes, and lungs. However, bone metastases develop in over 90% of patients, manifesting as metastatic bone disease. As Figure 2A illustrates, bone metastasis in prostate cancer follows a multi-step process: malignant transformation of healthy prostatic tissue, tumour growth inducing angiogenesis, and breakthrough of the basement membrane. Cancer cells then enter the bloodstream and travel through the circulatory or lymphatic systems to distant tissues. In circulation, these individual cancer cells cross the vascular wall in response to recruitment signals like CXCL12 secreted by target organs, entering the target organ's microenvironment.

Prostate cancer's strong tendency toward bone metastasis results from two key mechanisms. First, bone matrix cells secrete CXCL12, which binds to CXCR4 receptors on prostate cancer cell surfaces, guiding their migration to bone tissue. Second, cancer cells express high levels of integrin αvβ3, which binds to fibronectin in the bone matrix, enabling bone colonization [9].

Once established in bone tissue, prostate cancer cells create osteoblastic bone lesions through a "vicious cycle," while also indirectly stimulating osteolytic damage—creating mixed lesions that are predominantly osteoblastic. Tumour cells release factors such as WNT, IGFs, and FGFs that trigger osteoblast maturation and hyperproliferation. These osteoblasts then release factors like RANKL that promote the differentiation and maturation of osteoclast precursors. Simultaneously, tumour cells secrete osteolytic factors including RANKL, IL-6, and IL-8, causing osteoclast-mediated bone damage. This process releases cytokines from the bone matrix, such as TGF-β and IGFs, which further stimulate tumour cell proliferation [10].

To disrupt this vicious cycle, bisphosphonates are used to inhibit osteoclasts. Compounds like Ibandronate Sodium and Zoledronic acid monohydrate bind to hydroxyapatite in the bone matrix and are absorbed by osteoclasts, inhibiting the FDPS signalling pathway and triggering osteoclast death. Additionally, Denosumab, a human monoclonal antibody that inhibits RANKL, blocks osteoclast activation and survival, inducing osteoclast apoptosis and breaking the cycle of bone metastasis [10].

Figure 2. Prostate cancer bone meastasis and targeted therapies [9][10].

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To support researchers, AmBeed Life Science provides high-quality reagents critical for studying prostate cancer progression and therapeutic interventions:

· Chemokine & Receptors
· Osteoclasts/Bone/Osteogenesis Specific Modulators
· Denosumab: A human monoclonal antibody targeting RANKL, preventing osteoclast activation and bone destruction.

References

[1]J Clin Oncol. 2018 Apr 10;36(11):1080-1087.

[2]Cell Death Dis. 2024 Aug 1;15(8):558.

[3]Prostate Cancer Prostatic Dis. 2023 Jun;26(2):293-301.

[4]J Comput Aided Mol Des. 2016 Dec;30(12):1189-1200.

[5]Cancer Discov. 2017 Jul;7(7):736-749.

[6]Science. 2025 Sep 4;389(6764):eadv2367.

[7]Cancer Treat Rev. 2022 Mar;104:102359.

[8]Trends Cancer. 2020 Aug;6(8):702-715.

[9]Endocr Relat Cancer. 2023 Jul 25;30(9):e220360.

[10]Signal Transduct Target Ther. 2022 Jun 24;7(1):198.

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