Molecular Mechanisms of Enzalutamide Resistance in Prostate Cancer

Abstract

Purpose of ReviewCompensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in prostate cancer. After hydroxyflutamide and bicalutamide were used in therapy of prostate cancer over many years, novel anti-androgen enzalutamide showed improved clinical activity. However, enzalutamide resistance develops over a certain time period, and molecular mechanisms responsible for this process are heterogeneous.Research FindingsAs with other anti-androgens, these mechanisms include alterations of AR but also may be associated with overexpression of oncogenes which should be targeted by novel therapies. Androgen receptor splice variants have been frequently described in patients who developed enzalutamide resistance. Mutant AR F876L has been detected in patients who are resistant to enzalutamide. Glucocorticoid receptor overexpression has been observed in patient tissues and in pre-clinical models of enzalutamide resistance.SummaryThere is a heterogeneous picture of enzalutamide resistance in prostate cancer and, therefore, the development of appropriate post-enzalutamide treatment remains a challenge.

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

“…As opposed to CTCF-like and ETS-like motifs, c-MYC DNA-binding motifs were exclusively enriched in open chromatin regions found in CRPC samples , which is in agreement with several studies suggesting that, although c-MYC activity may be responsible for tumorigenesis, MYC oncogenic activation is a late event in PC progression and is involved in CRPC emergence (Nupponen et al 1998, Gurel et al 2008, Ahmadiyeh et al 2010, Hawksworth et al 2010, Koh et al 2010. Other TF motifs were also enriched in open chromatin regions of CRPC specimens, including glucocorticoid receptor (GR) motifs , which is in agreement with recent data showing its reactivation in CRPC (Arora et al 2013, Isikbay et al 2014, Kroon et al 2016, Culig 2017, Puhr et al 2018.…”

“…Antiandrogens such as enzalutamide and apalutamide, and drugs targeting hormone synthesis, such as abiraterone, have offered a survival benefit for men with CRPC. Like for ADT, however, resistance towards these drugs is predictable and can manifest as distinct molecular disease subtypes with varying dependency on the AR signaling axis (Bluemn et al 2017, Culig 2017.…”

Cancer-associated fibroblasts promote prostate tumor growth and progression through upregulation of cholesterol and steroid biosynthesis

“…Investigating how the tumor cells manage to develop escape mechanisms against these therapies is very important. Resistance to antiandrogens has been previously associated with expression of constitutively active AR variants lacking the ligand-binding domain, overexpression of several other oncogenes like glucocorticoid receptor (GR), NFkB, signal transducer and activator of transcription 3 (STAT3), Snail and Twist, and mutations within the AR gene (AR F876 L), which convert antiandrogens into agonists (reviewed by [10]). Overall, however, the mechanisms underlying antiandrogen resistances are still incompletely understood.…”

Epigenetic Regulation by Androgen Receptor in Prostate Cancer

“…Suppressing circulating testosterone to castration levels for the treatment of advanced prostate cancer does not decrease androgens sufficiently from the prostate tumor microenvironment [2,3,17]; therefore, AR remains active in CRPC tumors, and residual androgen levels remain within the range capable of activating AR [1,2,17,18]. Persistent AR activation provides a compelling rationale for developing more effective strategies to inhibit AR signals [18][19][20][21][22][23]. A new type of drug, called abiraterone acetate, which targets androgen synthesis and is a potent inhibitor of CYP17, blocks testosterone production from cholesterol [19].…”

“…Mechanistically, it is an AR blocker that inhibits AR nuclear translocation, DNA binding, and interaction with co-activators. Although these new drugs show impressive results, a majority of CRPC cases eventually develop resistance to the drugs [22]. Another new AR blocker, apalutamide (ARN-509), is under development for the treatment of CRPC.…”