mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Sun, Shi‐Yong

doi:10.1007/s11684-020-0812-7

Cited by 41 publications

(31 citation statements)

References 98 publications

(145 reference statements)

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“…It is reported that targeting mTOR activates the mediators involved in the PI3K or other signaling pathways. 45,46 For example, rapalogs increase AKT phosphorylation while suppressing mTORC1 function. Moreover, mTOR inhibition is reported to activate MAPK/ERK signaling in cancer cells.…”

Section: Mirna and Leukemiasmentioning

confidence: 99%

“…There are several reasons for failure of these drugs. It is reported that targeting mTOR activates the mediators involved in the PI3K or other signaling pathways 45,46 . For example, rapalogs increase AKT phosphorylation while suppressing mTORC1 function.…”

Section: Mirna and Pi3 Kinase Signaling In Hematopoietic Cancersmentioning

confidence: 99%

“…For example, rapalogs increase AKT phosphorylation while suppressing mTORC1 function. Moreover, mTOR inhibition is reported to activate MAPK/ERK signaling in cancer cells 46 . The existence of an intertwined signaling network seems to pose serious challenges to the use of mTOR inhibitors.…”

Section: Mirna and Pi3 Kinase Signaling In Hematopoietic Cancersmentioning

confidence: 99%

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PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role

Roshandel

Noorazar

Farhadihosseinabadi

et al. 2021

Clinical Laboratory Analysis

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Hematopoietic cancers are among the most common malignancies worldwide, which are divided into different types depending on the origin of tumor cells. In recent years, the pivotal role of different signaling pathways in the onset and progression of these cancer types has been well established. One of these pathways, whose role in blood malignancies has been well-defined, is PI3K/mTOR/AKT axis. The signaling pathway involves in a wide variety of important biological events in cells. It is clear that dysregulation of mediators involved in PI3 kinase signaling takes a pivotal role in cancer development. Considering the undeniable role of miRNAs, as one of the well-known families of non-coding RNAs, in gene regulation, we aimed to review the role of miR-NAs in regulation of PI3 kinase signaling effectors in hematopoietic cancers.

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Section: Mirna and Leukemiasmentioning

confidence: 99%

Section: Mirna and Pi3 Kinase Signaling In Hematopoietic Cancersmentioning

confidence: 99%

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PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role

Roshandel

Noorazar

Farhadihosseinabadi

et al. 2021

Clinical Laboratory Analysis

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“…Uncovering the mTORC2 mechanism has important ramifications for the use of mTOR inhibitors in the clinic for cancer: these inhibitors will prevent the phosphorylation of PKC and cause its loss, compromising the utility of these drugs (Sun, 2021). However, elucidation of the function of mTORC2 in relieving PKC dimerization unveils a potential approach to desensitize PKC to mTOR inhibitors.…”

Section: Therapeutic Implications For Novel Agc Activation Mechanismsmentioning

confidence: 99%

mTOR Regulation of AGC Kinases: New Twist to an Old Tail

Baffi

Newton

2021

Mol Pharmacol

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The family of AGC kinases not only regulate cellular biology by phosphorylating substrates, but are themselves controlled by phosphorylation. Phosphorylation generally occurs at two conserved regions in these kinases: a loop near the entrance to the active site, termed the activation loop, that correctly aligns residues for catalysis, and a C-terminal tail whose phosphorylation at a site termed the hydrophobic motif stabilizes the active conformation.Whereas phosphorylation of the activation loop is well established to be catalyzed by the phosphoinositide-dependent kinase 1 (PDK1), the mechanism of phosphorylation of the C-tail hydrophobic motif has been controversial. For a subset of AGC kinases, which includes most protein kinase C (PKC) isozymes and Akt, phosphorylation of the hydrophobic motif in cells was shown to depend on mTORC2 over 15 years ago, yet whether by direct phosphorylation or by another mechanism has remained elusive. The recent identification of a novel and evolutionarily conserved phosphorylation site on the C-tail termed the TOR-Interaction Motif (TIM) has finally unraveled the mystery of how mTORC2 regulates its client kinases. mTORC2 does not directly phosphorylate the hydrophobic motif, rather it converts kinases such as PKC and Akt into a conformation that can ultimately autophosphorylate at the hydrophobic motif.Identification of the direct mTOR phosphorylation that facilitates auto-regulation of the C-tail hydrophobic motif revises the activation mechanisms of mTOR-regulated AGC kinases. This new twist to an old tail opens avenues for therapeutic intervention.Significance Statement: The enzyme mTORC2 has been an enigmatic regulator of AGC kinases such as protein kinase C (PKC) and Akt. The recent discovery of a motif named the TOR

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“…With the gradual deepening of understanding, it had been found that there were feedbacks of multiple kinases during the employment of Everolimus, such as hyperphosphorylation of eIF4E at the Ser209 site, which led to the development of drug resistance 15 . The mTOR inhibitor Rapalog induced eIF4E phosphorylation was done by kinases termed MAP kinase-interacting kinases (Mnks) independently of the conventional Mnk-activating MAPK pathway 16 .…”

Section: Loss Of Intracellular Mir-7-5p Induces Phosphorylation Of Mnk/eif4e Axis But Supplement Of Extra Exosomal Mir-7-5p Can Reverse Imentioning

confidence: 99%

Everolimus-Induced Loss of Exosomal miR-7-5p Activates MNK/eIF4E Axis in Non-Small Cell Lung Cancer

Liu

Wang

Ning

et al. 2021

Preprint

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Background: Everolimus is a kind of mTOR inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer cells (NSCLC). Typically, eIF4E phosphorylation increased by mTOR inhibitors was mainly mediated by MNKs. But the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposing. Our previous studies have found that tumor suppressor miR-7-5p was loss in A549 cells after treatment of Everolimus. Exactly, MNK1 is the target of miR-7-5p. Here, we analyzed levels and functions of miR-7-5p in the usage of Everolimus in NSCLC.Methods: miR-7-5p level and expression of main markers of MNK/eIF4E axis was evaluated by qRT-PCR, in situ hybridization, and immunohistochemistry on human NPC samples, and by RT-PCR, western blot on NPC cell lines. Proliferation, migration and invasion of NPC cells in culture were assessed by Colony formation, CCK-8, Wound healing and Transwell assays. NPC cell tumorigenicity was assessed by xenotransplants in nude mice. Targeted binding of miR-7-5p to MNK1 was confirmed by the Dual-luciferase reporter assay. And the isolation and identification of exosomes were invested by Invitrogen™ Total Exosome RNA Isolation Kit, western blot, transmission electron microscopy and Zetasizer Nano ZS90 instrument.Results: Everolimus stimulatedtherelease of miR-7-5p loaded exosomes from NSCLC cellsinRab27A and Rab27B dependent manners, thereby reducing the intracellular tumor suppressor miR-7-5p to attenuate the inhibition of MNK1 and promote MNK-dependent eIF4E phosphorylation. Of note, both lower miR-7-5p and positive MNK1 could act as independent poor prognostic biomarkers for NSCLC. And delivery of miR-7-5p would inhibit the poor prognosis of it. Bothendogenous miR-7-5p-5p or exo-miR-7-5p collaborated with Everolimus, not only inhibited the proliferation, migration, and metastasisof NSCLC in vitro and in vivo, but also promoted the apoptosis of NSCLC viatargeting MNK/eIF4E axis.Conclusion: Everolimus-induced loss of exosomal miR-7-5p activates MNK/eIF4E axis to blunt effectiveness of itself in NSCLC. Therefore, delivery of miR-7-5p could act as a combined therapeutic strategy for mTOR-targeted cancer therapy and prognosis.

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Cited by 41 publications

References 98 publications

PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role

PI3 kinase signaling pathway in hematopoietic cancers: A glance in miRNA's role

mTOR Regulation of AGC Kinases: New Twist to an Old Tail

Everolimus-Induced Loss of Exosomal miR-7-5p Activates MNK/eIF4E Axis in Non-Small Cell Lung Cancer

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