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Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment

The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in t...

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Autores principales: Raith, Fabio, O’Donovan, Daniel H., Lemos, Clara, Politz, Oliver, Haendler, Bernard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917236/
https://www.ncbi.nlm.nih.gov/pubmed/36768610
http://dx.doi.org/10.3390/ijms24032289
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author Raith, Fabio
O’Donovan, Daniel H.
Lemos, Clara
Politz, Oliver
Haendler, Bernard
author_facet Raith, Fabio
O’Donovan, Daniel H.
Lemos, Clara
Politz, Oliver
Haendler, Bernard
author_sort Raith, Fabio
collection PubMed
description The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in the AR pathway, such as gene amplification or mutations, and also the emergence of alternative pathways that render the tumor less or, more rarely, completely independent of androgen activation. An essential oncogenic axis activated in prostate cancer is the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, as evidenced by the frequent alterations of the negative regulator phosphatase and tensin homolog (PTEN) and by the activating mutations in PI3K subunits. Additionally, crosstalk and reciprocal feedback loops between androgen signaling and the PI3K/AKT/mTOR signaling cascade that activate pro-survival signals and play an essential role in disease recurrence and progression have been evidenced. Inhibitors addressing different players of the PI3K/AKT/mTOR pathway have been evaluated in the clinic. Only a limited benefit has been reported in prostate cancer up to now due to the associated side effects, so novel combination approaches and biomarkers predictive of patient response are urgently needed. Here, we reviewed recent data on the crosstalk between AR signaling and the PI3K/AKT/mTOR pathway, the selective inhibitors identified, and the most advanced clinical studies, with a focus on combination treatments. A deeper understanding of the complex molecular mechanisms involved in disease progression and treatment resistance is essential to further guide therapeutic approaches with improved outcomes.
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spelling pubmed-99172362023-02-11 Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment Raith, Fabio O’Donovan, Daniel H. Lemos, Clara Politz, Oliver Haendler, Bernard Int J Mol Sci Review The reduction in androgen synthesis and the blockade of the androgen receptor (AR) function by chemical castration and AR signaling inhibitors represent the main treatment lines for the initial stages of prostate cancer. Unfortunately, resistance mechanisms ultimately develop due to alterations in the AR pathway, such as gene amplification or mutations, and also the emergence of alternative pathways that render the tumor less or, more rarely, completely independent of androgen activation. An essential oncogenic axis activated in prostate cancer is the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, as evidenced by the frequent alterations of the negative regulator phosphatase and tensin homolog (PTEN) and by the activating mutations in PI3K subunits. Additionally, crosstalk and reciprocal feedback loops between androgen signaling and the PI3K/AKT/mTOR signaling cascade that activate pro-survival signals and play an essential role in disease recurrence and progression have been evidenced. Inhibitors addressing different players of the PI3K/AKT/mTOR pathway have been evaluated in the clinic. Only a limited benefit has been reported in prostate cancer up to now due to the associated side effects, so novel combination approaches and biomarkers predictive of patient response are urgently needed. Here, we reviewed recent data on the crosstalk between AR signaling and the PI3K/AKT/mTOR pathway, the selective inhibitors identified, and the most advanced clinical studies, with a focus on combination treatments. A deeper understanding of the complex molecular mechanisms involved in disease progression and treatment resistance is essential to further guide therapeutic approaches with improved outcomes. MDPI 2023-01-24 /pmc/articles/PMC9917236/ /pubmed/36768610 http://dx.doi.org/10.3390/ijms24032289 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Raith, Fabio
O’Donovan, Daniel H.
Lemos, Clara
Politz, Oliver
Haendler, Bernard
Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment
title Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment
title_full Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment
title_fullStr Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment
title_full_unstemmed Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment
title_short Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment
title_sort addressing the reciprocal crosstalk between the ar and the pi3k/akt/mtor signaling pathways for prostate cancer treatment
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9917236/
https://www.ncbi.nlm.nih.gov/pubmed/36768610
http://dx.doi.org/10.3390/ijms24032289
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