PMID- 35366325
OWN - NLM
STAT- MEDLINE
DCOM- 20220510
LR  - 20230403
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 163
IP  - 6
DP  - 2022 Jun 1
TI  - Targeting mTOR in the Context of Diet and Whole-body Metabolism.
LID - 10.1210/endocr/bqac041 [doi]
LID - bqac041
AB  - The mechanistic target of the rapamycin (mTOR) signaling pathway is the central 
      regulator of cell growth and proliferation by integrating growth factor and 
      nutrient availability. Under healthy physiological conditions, this process is 
      tightly coordinated and essential to maintain whole-body homeostasis. Not 
      surprisingly, dysregulated mTOR signaling underpins several diseases with 
      increasing incidence worldwide, including obesity, diabetes, and cancer. 
      Consequently, there is significant clinical interest in developing therapeutic 
      strategies that effectively target this pathway. The transition of mTOR 
      inhibitors from the bench to bedside, however, has largely been marked with 
      challenges and shortcomings, such as the development of therapy resistance and 
      adverse side effects in patients. In this review, we discuss the current status 
      of first-, second-, and third-generation mTOR inhibitors as a cancer therapy in 
      both preclinical and clinical settings, with a particular emphasis on the 
      mechanisms of drug resistance. We focus especially on the emerging role of diet 
      as an important environmental determinant of therapy response, and posit a 
      conceptual framework that links nutrient availability and whole-body metabolic 
      states such as obesity with many of the previously defined processes that drive 
      resistance to mTOR-targeted therapies. Given the role of mTOR as a central 
      integrator of cell metabolism and function, we propose that modulating nutrient 
      inputs through dietary interventions may influence the signaling dynamics of this 
      pathway and compensatory nodes. In doing so, new opportunities for exploiting 
      diet/drug synergies are highlighted that may unlock the therapeutic potential of 
      mTOR inhibitors as a cancer treatment.
CI  - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the 
      Endocrine Society. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Koundouros, Nikos
AU  - Koundouros N
AUID- ORCID: 0000-0001-8378-9673
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021,USA.
AD  - Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
FAU - Blenis, John
AU  - Blenis J
AUID- ORCID: 0000-0003-3622-2337
AD  - Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021,USA.
AD  - Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
AD  - Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA.
LA  - eng
GR  - R01 GM051405/GM/NIGMS NIH HHS/United States
GR  - R01 CA046595/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Diet
MH  - Humans
MH  - Obesity/drug therapy
MH  - *Signal Transduction
MH  - Sirolimus/pharmacology
MH  - *TOR Serine-Threonine Kinases/metabolism
PMC - PMC9391686
OTO - NOTNLM
OT  - diet
OT  - drug resistance
OT  - mTOR
OT  - metabolism
EDAT- 2022/04/03 06:00
MHDA- 2022/05/11 06:00
PMCR- 2023/04/02
CRDT- 2022/04/02 17:04
PHST- 2022/02/24 00:00 [received]
PHST- 2022/04/03 06:00 [pubmed]
PHST- 2022/05/11 06:00 [medline]
PHST- 2022/04/02 17:04 [entrez]
PHST- 2023/04/02 00:00 [pmc-release]
AID - 6562776 [pii]
AID - bqac041 [pii]
AID - 10.1210/endocr/bqac041 [doi]
PST - ppublish
SO  - Endocrinology. 2022 Jun 1;163(6):bqac041. doi: 10.1210/endocr/bqac041.