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Targeting molecular resistance in castration-resistant prostate cancer.

Chandrasekar T, Yang JC, Gao AC, Evans CP - BMC Med (2015)

Bottom Line: Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone.While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly.Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, Davis, USA. tchandrasekar@ucdavis.edu.

ABSTRACT
Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

No MeSH data available.


Related in: MedlinePlus

Androgen receptor-dependent mechanisms of resistance in hormone-naïve prostate cancer leading to castration-resistance, and role of current FDA-approved therapies. wtAR, Wild-type androgen receptor; ARV, Androgen receptor variant; mutAR, Mutated androgen receptor; T, Testosterone; DHT, Dihydrotestosterone
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Fig1: Androgen receptor-dependent mechanisms of resistance in hormone-naïve prostate cancer leading to castration-resistance, and role of current FDA-approved therapies. wtAR, Wild-type androgen receptor; ARV, Androgen receptor variant; mutAR, Mutated androgen receptor; T, Testosterone; DHT, Dihydrotestosterone

Mentions: The mechanisms by which hormone-sensitive prostate cancer progresses to CRPC have been studied extensively. They can be subcategorized into five general categories – AR amplification and mutation, co-activator and co-repressor modifications, aberrant activation/post-translational modification, altered steroidogenesis, and AR splice variants. AR amplification, which allows continued androgen-axis activation in the presence of low levels of androgens in the prostate microenvironment, is found in 30–80 % of CRPC cell lines [15, 16]. AR point mutations lead to increased AR activity in the same microenvironment, but also broaden the ligand pool to which AR responds, including non-androgenic steroids [17–23]. Over 150 molecules have been identified as co-activators and co-repressors to the AR, and mutations in various components in the coregulator complex have been shown to improve androgen-stimulated AR activation and lead to progression of disease [24–27]. Aberrant activation encompasses pathways that activate AR in a ligand-independent manner [28–30]. Alterations in the steroidogenesis pathways allow prostate cancer cells to bypass testosterone, and utilize adrenal androgens to generate the functionally more potent DHT via the 5α-dione pathway [31–35]. Androgen receptor splice variants (ARV), which will be addressed in more detail later, are constitutively active modifications of the wild type AR. Figure 1 reviews the androgen axis and currently approved therapies.Fig. 1


Targeting molecular resistance in castration-resistant prostate cancer.

Chandrasekar T, Yang JC, Gao AC, Evans CP - BMC Med (2015)

Androgen receptor-dependent mechanisms of resistance in hormone-naïve prostate cancer leading to castration-resistance, and role of current FDA-approved therapies. wtAR, Wild-type androgen receptor; ARV, Androgen receptor variant; mutAR, Mutated androgen receptor; T, Testosterone; DHT, Dihydrotestosterone
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4556222&req=5

Fig1: Androgen receptor-dependent mechanisms of resistance in hormone-naïve prostate cancer leading to castration-resistance, and role of current FDA-approved therapies. wtAR, Wild-type androgen receptor; ARV, Androgen receptor variant; mutAR, Mutated androgen receptor; T, Testosterone; DHT, Dihydrotestosterone
Mentions: The mechanisms by which hormone-sensitive prostate cancer progresses to CRPC have been studied extensively. They can be subcategorized into five general categories – AR amplification and mutation, co-activator and co-repressor modifications, aberrant activation/post-translational modification, altered steroidogenesis, and AR splice variants. AR amplification, which allows continued androgen-axis activation in the presence of low levels of androgens in the prostate microenvironment, is found in 30–80 % of CRPC cell lines [15, 16]. AR point mutations lead to increased AR activity in the same microenvironment, but also broaden the ligand pool to which AR responds, including non-androgenic steroids [17–23]. Over 150 molecules have been identified as co-activators and co-repressors to the AR, and mutations in various components in the coregulator complex have been shown to improve androgen-stimulated AR activation and lead to progression of disease [24–27]. Aberrant activation encompasses pathways that activate AR in a ligand-independent manner [28–30]. Alterations in the steroidogenesis pathways allow prostate cancer cells to bypass testosterone, and utilize adrenal androgens to generate the functionally more potent DHT via the 5α-dione pathway [31–35]. Androgen receptor splice variants (ARV), which will be addressed in more detail later, are constitutively active modifications of the wild type AR. Figure 1 reviews the androgen axis and currently approved therapies.Fig. 1

Bottom Line: Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone.While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly.Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, Davis, USA. tchandrasekar@ucdavis.edu.

ABSTRACT
Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

No MeSH data available.


Related in: MedlinePlus