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    • br Prostate cancer and resistance to AR targeting treatment

    2024-03-16


    Prostate cancer and resistance to AR targeting treatment The AR plays a pivotal role in the development, differentiation, homeostasis and secretory function of the normal prostate (Wilson, 2011). The AR is also a key player in many phases of prostate carcinogenesis (Huggins et al., 1941, Scher and Sawyers, 2005). The androgen deprivation therapy (ADT), which is lowering the levels of circulating androgens, is effective for most patients. However, after the initial good response, the disease will progress into what is called mCRPC. Surprisingly, at this stage of the disease the AR signaling pathway is reactivated, and it can be treated with compounds that block AR signaling either directly as antagonists of the AR protein (e.g. Enzalutamide, ARN-509) or indirectly via blocking androgen biosynthesis (e.g. Abiraterone acetate) (Helsen et al., 2014). These treatments are at first quite effective and have been shown to prolong the overall survival of mCRPC patients (Attard et al., 2009a, Attard et al., 2009b, Cabot et al., 2012, De Bono et al., 2011). However, again most patients ultimately progress as the cancer develops resistance towards these drugs. Multiple molecular mechanisms behind castration or anti-androgen resistance have been proposed (reviewed in (Claessens et al., 2014, Lorente et al., 2015, Shtivelman et al., 2014)). Surprisingly, reactivation of the androgen signaling axis explains how PCa KU-55933 survive in the absence of androgens or even in the presence of anti-androgens. The most common mechanisms are depicted in Fig. 1. The AR gene can be amplified resulting in AR overexpression and persistent signaling (Palmberg et al., 1996). The AR gene amplifications and accompanied higher expression levels have been correlated with aggressiveness and therapy response in CRPC (Koivisto et al., 1997, Visakorpi et al., 1995). The concomitant increase in AR protein levels may lead to a sustained signaling under ADT conditions, when circulating androgens concentration is lowered considerably (Cai et al., 2011). Even in the presence of anti-androgens, or androgen synthesis inhibitors, it is well-known that increased AR levels can confer resistance possibly because of partial agonism of the antagonists (Palmberg et al., 1996, Robinson et al., 2015). However, it is also possible that this overexpression produces more splice variants that lack the LBD (discussed below), thus escaping the control by anti-androgens (Wyatt et al., 2016). Alternative splicing can result in the truncation of the ligand binding domain, and this will result in a constitutively active transcription factor (Guo and Qiu, 2011). While there is a strong correlation between enhanced AR expression and the detection of splice variants, others have detected genomic events that also can lead to expression of AR truncations (Li et al., 2012). In contrast to cells with genomic AR truncations, cells with aberrant splicing can co-express full size together with AR splice variants. The variants (primarily AR-V7) were first shown to emerge in metastatic PCa after androgen deprivation as well as anti-androgen treatment (Hu et al., 2009). It is likely that cells expressing the splice variants lacking the LBD escape the selective pressure on the AR axis. Clearly such a truncated receptor retains DNA binding and most of its transactivation properties but lost its ligand control (Claessens et al., 2014). Alternatively, the AR can be mutated, which results in gain of functions rendering the receptor either promiscuous for antagonists or other hormones, or hypersensitive to androgens (Chandrasekar et al., 2015). The majority of the mutations found in PCa are missense mutations in the LBD, while NTD and DBD mutations are less frequent (Gottlieb et al., 2012, Koochekpour, 2010). Interestingly, one PCa mutation that resides in the LBD dimer interface was proposed to have a stabilizing effect, thus adding another possible mechanism of resistance (Nadal et al., 2017).