PMID- 36768610
OWN - NLM
STAT- MEDLINE
DCOM- 20230214
LR  - 20230214
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 3
DP  - 2023 Jan 24
TI  - Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR 
      Signaling Pathways for Prostate Cancer Treatment.
LID - 10.3390/ijms24032289 [doi]
LID - 2289
AB  - 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.
FAU - Raith, Fabio
AU  - Raith F
AUID- ORCID: 0000-0002-7235-8453
AD  - Research & Development, Pharmaceuticals, Bayer AG, Mullerstr. 178, 13353 Berlin, 
      Germany.
FAU - O'Donovan, Daniel H
AU  - O'Donovan DH
AD  - Research & Development, Pharmaceuticals, Bayer AG, Mullerstr. 178, 13353 Berlin, 
      Germany.
FAU - Lemos, Clara
AU  - Lemos C
AUID- ORCID: 0000-0002-3604-3323
AD  - Bayer Research and Innovation Center, Bayer US LLC, 238 Main Street, Cambridge, 
      MA 02142, USA.
FAU - Politz, Oliver
AU  - Politz O
AUID- ORCID: 0000-0002-0272-6249
AD  - Research & Development, Pharmaceuticals, Bayer AG, Mullerstr. 178, 13353 Berlin, 
      Germany.
FAU - Haendler, Bernard
AU  - Haendler B
AUID- ORCID: 0000-0002-4490-0663
AD  - Research & Development, Pharmaceuticals, Bayer AG, Mullerstr. 178, 13353 Berlin, 
      Germany.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20230124
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Receptors, Androgen)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - 0 (Androgens)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
SB  - IM
MH  - Male
MH  - Humans
MH  - *Receptors, Androgen/genetics/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Androgens/pharmacology
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Prostatic Neoplasms/drug therapy/genetics/metabolism
PMC - PMC9917236
OTO - NOTNLM
OT  - AKT
OT  - PI3K
OT  - androgen receptor
OT  - mTOR
OT  - prostate cancer
COIS- The authors are employees and own shares of Bayer.
EDAT- 2023/02/12 06:00
MHDA- 2023/02/15 06:00
PMCR- 2023/01/24
CRDT- 2023/02/11 01:21
PHST- 2022/12/22 00:00 [received]
PHST- 2023/01/17 00:00 [revised]
PHST- 2023/01/20 00:00 [accepted]
PHST- 2023/02/11 01:21 [entrez]
PHST- 2023/02/12 06:00 [pubmed]
PHST- 2023/02/15 06:00 [medline]
PHST- 2023/01/24 00:00 [pmc-release]
AID - ijms24032289 [pii]
AID - ijms-24-02289 [pii]
AID - 10.3390/ijms24032289 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Jan 24;24(3):2289. doi: 10.3390/ijms24032289.