Laboratory-Clinic InterfaceUnderstanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer
Introduction
With nearly 220,000 new cases expected in the USA in 2015, prostate cancer (PC) represents the most frequent type of cancer in men, accounting for almost 26% of new cancer cases [1]. Despite most of the new patients are diagnosed in early stage, approximately 4% of the cases at baseline are in advanced stage and some patients treated initially with radical surgery will subsequently relapse.
Since the seminal work of Huggins and Hodges [2], androgen deprivation therapy (ADT), either surgical or biochemical, has been the mainstay of treatment for relapsed and metastatic PC patients, due to the driving role of androgen receptor (AR) in the development of these tumors.
Despite the initial high response rates, many patients become castrate-resistant within 3 years from the start of ADT and, consequently, there is a growing interest in testing new agents and strategies to overcome acquired resistance.
Recently it has been shown that, in castration resistant PC (CRPC) patients, even small concentrations of extra-gonadal androgens persisting despite ADT could activate the AR pathway and that PC cells could synthesize their own androgens [3]. Following these observations, a renewed interest on the AR signaling pathway was generated, and a second generation of hormonal therapies has been developed.
Abiraterone acetate is an oral drug that selectively and irreversibly inhibits the CYP17A1 microsomal enzyme, leading to the inhibition of testosterone biosynthesis in adrenal glands, in testis and in PC cells. Enzalutamide is an oral AR antagonist with an 8-fold higher affinity for its target than bicalutamide, preventing also AR nuclear translocation and DNA binding.
In CRPC, patients pretreated with docetaxel, two phase III trials, COU-AA-301 and AFFIRM, showed an improvement in overall survival (OS) with abiraterone (median OS 14.8 vs 10.9 months; hazard ratio [HR] 0.65, 95% CI, 0.54–0.77; p < 0.001) [4] and enzalutamide (median OS 18.4 vs 13.6 months; HR 0.63, 95% CI, 0.53–0.75; p < 0.001) [5], respectively. More recently, the COU-AA-302 study confirmed the efficacy of abiraterone in asymptomatic and mildly symptomatic chemotherapy-naive metastatic CRPC patients in terms of OS (median OS 34.7 vs 30.3 months; HR: 0.81, 95% CI, 0.70–0.93; p = 0.0033) [6].
In the PREVAIL study, enzalutamide showed a statistically significant 29% reduction in the risk of death (HR 0.70, 95% CI, 0.59–0.83; p = 0.0001) and an 81% reduction in the risk of radiographic progression compared to placebo (HR 0.19; CI 95%, 0.15–0.23; p < 0.0001) [7].
Based on these data, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted approval for abiraterone for the treatment of both docetaxel-naive and docetaxel-pretreated CRPC patients and for enzalutamide in the post-docetaxel setting.
Despite the inhibitory properties of these agents, PC cells, even after initial response, become resistant and cause clinical disease progression, posing the question how to deal with acquired resistance. In this paper we will review the putative mechanisms of primary and acquired resistance to new hormonal agents and some potential new strategies to overcome it.
Section snippets
Physiological androgen synthesis
In adult men, testosterone (T) and 5-α-dihydrotestosterone (DHT), mainly produced in the testes, with only 5–10% being synthesized from the adrenal glands, are the commonest forms of endogenous androgens and the major physiological AR ligands. Other steroid hormones, also produced by the adrenal glands, such as androstenedione and dehydroepiandrosterone (DHEA), can bind the AR.
In peripheral tissues, weak adrenal androgens such as DHEA-sulfate (DHEA-S) can be reduced to T, even if this
The androgen receptor
The AR gene is located on chromosome Xq11–12 and accounts for eight exons. AR is a 110-kDa nuclear protein that contains 918 acid residues and binds a specific hormone response element (HRE) known as androgen response element (ARE). AR is formed by different domains: the N-terminal domain (NTD), the DNA-binding domain (DBD), the hinge region and the ligand-binding domain (LBD) [9].
Once activated, AR binds AREs as a dimer. There are two different AREs: the inverted repeat AREs, that bind and
The adaptive response to androgen deprivation
Recently, a significant shift in the understanding of natural history of PC has occurred and it is currently known that castration resistance does not necessarily results in resistance to hormonal agents. In fact, despite the dramatic decrease of serum T induced by ADT, CRPC remains driven by AR signaling, being able to overexpress androgen dependent genes [13].
Multiple mechanisms have been identified to explain this phenomenon, including AR gene mutation [14], AR gene overexpression [15], AR
The mechanisms of resistance to abiraterone or enzalutamide
Despite the demonstrated benefits of both abiraterone and enzalutamide, some CRPC patients are primary resistant and do not respond to treatment, the gain in progression-free survival and OS obtained with these therapies is clinically relevant but limited, and the appearance of acquired resistance is the rule for all treated patients.
Although primary resistance has been defined by some authors as the absence of PSA reduction [25], a commonly accepted definition of primary resistance is a
Discussion
In the 1990s dedicated studies on AR in CRPC revealed escape mechanisms from androgen blockade through either mutation or amplification of AR [14]. Additionally, these resistance mechanisms corroborate the hypothesis that androgen-signaling remains biologically relevant despite castrate levels of testosterone and these observations guided the research and development of a new generation of androgen synthesis inhibitors and AR antagonists [4], [5].
However, primary and acquired resistance to new
Conclusion
Although during the past decade specific molecular alterations have been identified in the so called “oncogene addicted” tumors that led to the development of specific and effective targeted therapies that induce tumor shrinkage in most of the treated cases as well as significantly extend progression-free survival, the responses to these agents is limited by the onset of acquired resistance. A deeper understanding of resistance mechanisms to these drugs is essential to maximize their efficacy
Conflict of interest
None.
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