Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.
Level 5 - mechanism / opinion, no new human data
Narrative review of molecular mechanisms and therapeutic targets without original human data or systematic synthesis.
PubMed 38474373 · doi:10.3390/cells13050409
What was done
This narrative review synthesized literature on the regulation of the mechanistic target of rapamycin (mTOR) signaling pathways and its two multiprotein complexes, mTORC1 and mTORC2. It detailed their upstream modulation (including PI3K/Akt, nutrients, growth factors, and neurotransmitters), role in normal and cancer stem cell characteristics, contribution to multistep tumorigenesis, and pharmacological inhibition strategies comparing allosteric mTORC1 inhibitors (rapalogs) against dual-complex ATP-catalytic binding site inhibitors in cancers such as glioblastoma.
What was found
The abstract provides conceptual and mechanistic descriptions without quantitative data or numerical outcomes. It reported that mTORC1 is rapamycin-sensitive and tightly controlled by PI3K/Akt, nutrients, growth factors, and neurotransmitters, whereas mTORC2 is ribosome-associated, growth-factor-modulated, and rapamycin-insensitive. It noted that rapalogues only incompletely suppress mTORC1 via allosteric mechanisms, whereas ATP-catalytic site inhibitors block both mTORC1 and mTORC2.
Why it matters
The paper contextualizes why dual mTORC1/mTORC2 catalytic inhibitors are being developed to target cancer stem cells and overcome the incomplete pathway suppression achieved by first-generation rapalogues.
Limits
As a narrative review, it lacks a systematic search methodology, quantitative meta-analysis, and direct empirical data. The abstract provides no specific effect sizes, survival metrics, clinical response rates, or safety outcomes in human trials.
Cited by
- supports mTOR forms two distinct cellular complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).