Platinum Priority – Prostate CancerEditorial by Jens Adam Ceder on pp. 480–481 of this issueUnderstanding the Mechanisms of Androgen Deprivation Resistance in Prostate Cancer at the Molecular Level
Introduction
Prostate cancer (PCa) remains the second leading cause of death due to cancer in Western societies [1]. Usually PCa is diagnosed as localized disease, and its management includes surveillance or radical prostatectomy, radiation therapy, or even combination approaches such as hormonal therapy prior to prostatectomy. Few patients undergoing PCa screening present with metastatic disease, which is also present in ≥10% of unscreened populations at first presentation—usually in bone, the predominant site of advanced and lethal PCa [2]—highlighting critical differences between screened and unscreened populations.
Despite the obvious increase in overall survival of patients with PCa over the past decade, recent data indicate that improvement of survival among patients with metastatic PCa has not significantly contributed to this decline in mortality [3]. Patients with metastatic disease usually receive hormonal therapy that decreases the production of testosterone by the testes. However, after an initial response, which varies significantly among patients, the disease eventually progresses despite the low levels of testosterone in the systemic circulation (<20 ng/dl) [4]. This stage of disease is known as metastatic castration-resistant PCa (mCRPC); the average overall survival is 1.5 yr, with significant variability among patients with lymph node metastasis, bone metastasis, and metastasis in both lymph nodes and bone [3]. Docetaxel and cabazitaxel are the only chemotherapy regimens approved for this stage of the disease [5], [6]. Radium Ra 233 (Xofigo) injection was recently approved for the treatment of patients with castration-resistant PCa (CRPC), symptomatic bone metastases, and no known visceral metastatic disease [7].
Numerous studies during the last decade have highlighted the role of androgen receptor (AR) in the development of mCRPC, showing that despite systemic androgen depletion, AR signaling remains active and supports the survival and growth of PCa cells. Based on these results, two novel agents have been recently evaluated in clinical trials: abiraterone acetate (AA), an inhibitor of androgen synthesis, and enzalutamide, a potent antiandrogen.
AA is a CYP17A1 inhibitor blocking the production of androgens in the testes, adrenal glands, and tumor microenvironment by inhibiting both 17α-hydroxylase and 17,20 lyase activities of the CYP17A1 enzyme [8]. AA has been recently approved for chemotherapy-naive patients with mCRPC, improving overall survival by 4 mo [9].
Enzalutamide is a novel antagonist of AR, inhibiting nuclear translocation, chromatin binding, and interactions with AR coregulators [10]. Enzalutamide prolongs the survival of patients who failed chemotherapy [11], and more recent data suggest that in chemotherapy-naive mCRPC patients, enzalutamide increases overall and progression-free survival and delays the need for chemotherapy [12].
ARN-509, a next-generation antiandrogen, was found to be more effective than enzalutamide in CRPC preclinical models in terms of tumor growth [13]. According to a recent phase 1 clinical trial, ARN-509 is safe and well tolerated and displays dose-proportional pharmacokinetics demonstrating pharmacodynamic and antitumor activity across all dose levels examined [14].
Despite the significant advances in the targeting of AR that have been translated into survival improvement for patients with mCRPC, this stage of disease remains incurable and is associated with significant morbidity and mortality [15]. While the introduction of novel antiandrogens has provided survival benefits through tumor growth inhibition, two critical clinical concerns arise: (1) Which patients really benefit from these agents, and which biomarkers can be used to identify these patients? (2) What alternative approaches can be used if the disease progresses during treatment with these agents?
The aim of this review is to summarize the recent advances in the evaluation of the multiple levels of development of resistance to androgen deprivation and AR inhibition that occur before and after the introduction of novel antiandrogen axis agents. In PCa, the heterogeneity of the diversity of pathways involved demands a critical consideration of numerous possible explanations of these biological events.
Section snippets
Evidence acquisition
PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included.
Paracrine/autocrine androgen synthesis as a mechanism of resistance to systemic hormonal therapy and novel inhibitors of androgen biosynthesis
It is well documented that in normal prostate tissue and low-grade PCa, the prostate stroma secretes active androgens (eg, dihydrotestosterone [DHT]) and other growth factors supporting the survival and proliferation of overlying epithelium by a paracrine loop [16]. During PCa progression, this paracrine dependence is lost and converted to an autocrine phase in which cancer cells produce numerous factors, including androgens, supporting their own growth and survival [16]. Although circulating
Conclusions
Despite the introduction of novel agents targeting androgen action, mCRPC remains an incurable disease. Increased androgen biosynthesis in the tumor microenvironment and alterations of AR signaling (including AR mutations mainly in the LBD, AR variants, and AR gene amplifications) all play roles in the development of resistance to systemic hormonal therapy. Especially after the introduction of AA and enzalutamide, which maximally decrease AR activity, these and other mechanisms related to
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STAT3 signaling in prostate cancer progression and therapy resistance: An oncogenic pathway with diverse functions
2023, Biomedicine and PharmacotherapyMolecular Mechanisms of Castrate-Resistant Prostate Cancer
2022, Urologic Clinics of North AmericaCitation Excerpt :Post-translational AR modifications can enhance AR transcriptional activity at lower androgen levels.25 Such alterations, including phosphorylation (through ACK1, PIM-1, SRC, etc.), acetylation (through ARD1, p300, etc.), and methylation (through DOT1L, Set9, PRMT5, etc.) are associated with increased AR function,36 contributing to AR reactivation in the CR state and subsequent ARSI-resistance.37 Increased tyrosine phosphorylation in CRPC is mediated by kinases like SRC and ACK1 that are increased at low androgen levels.25
Fascin-1 expression is associated with neuroendocrine prostate cancer and directly suppressed by androgen receptor
2023, British Journal of Cancer