mTOR pathway and DNA damage response: A therapeutic strategy in cancer therapy

Pazhooh, Romina Danesh; Farnood, Parnia Rahnamay; Asemi, Zatollah; Mirsafaei, Liaosadat; Yousefi, Bahman; Mirzaei, Hamed

doi:10.1016/j.dnarep.2021.103142

Cited by 20 publications

(11 citation statements)

References 158 publications

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“…There is a bidirectional cross-talk between mTORC1 and DNA damage. Interestingly, most studies have placed mTORC1 upstream of DNA damage (Danesh Pazhooh et al, 2021; Ma et al, 2018), with only a handful demonstrating that ATR or ATM are upstream of mTORC1 activation (Alexander et al, 2010; Lamm et al, 2020). One prior report found that replication stress, and therefore ATR activity, promotes nuclear mTORC1 activation (Lamm et al, 2020), although no direct mechanism was identified.…”

Section: Discussionmentioning

confidence: 99%

“…Both ATR and ATM have roles in metabolism, which may promote cancer phenotypes, including nutrient uptake and nucleotide synthesis (Aird et al, 2015; Chen et al, 2020; Dahl and Aird, 2017; Diehl et al, 2022; Huang et al, 2023). It is therefore unsurprising that studies have previously linked both ATR and ATM to the nutrient sensor mTORC1 in a bidirectional fashion (Alexander et al, 2010; Danesh Pazhooh et al, 2021; Lamm et al, 2020; Ma et al, 2018). However, whether the DDR promotes specific metabolic rewiring to directly enhance mTORC1 signaling remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

Tangudu,

Huang,

Fang

et al. 2023

Preprint

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DNA damage and cellular metabolism are intricately linked with bidirectional feedback. Two of the main effectors of the DNA damage response and control of cellular metabolism are ATR and mTORC1, respectively. Prior work has placed ATR upstream of mTORC1 during replication stress, yet the direct mechanism for how mTORC1 is activated in this context remain unclear. We previously published that p16-low cells have mTORC1 hyperactivation, which in part promotes their proliferation. Using this model, we found that ATR, but not ATM, is upstream of mTORC1 activation via de novo cholesterol synthesis and is associated with increased lanosterol synthase (LSS). Indeed, p16-low cells showed increased cholesterol abundance. Additionally, knockdown of either ATR or LSS decreased mTORC1 activity. Decreased mTORC1 activity due to ATR knockdown was rescued by cholesterol supplementation. Finally, using both LSS inhibitors and multiple FDA-approved de novo cholesterol synthesis inhibitors, we found that the de novo cholesterol biosynthesis pathway is a metabolic vulnerability of p16-low cells. Together, our data provide new evidence coupling the DNA damage response and cholesterol metabolism and demonstrate the feasibility of using FDA-approved cholesterol-lowering drugs in tumors with loss of p16.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

Tangudu,

Huang,

Fang

et al. 2023

Preprint

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“…We also found the enrichment in DNA repair pathway by mTOR pathway mutation in tumors. In previous studies, mTOR pathway was reportedly to be interacted with DDR, including DNA repair pathway [ 35 , 36 ]. The link of mTOR pathway with DDR pathway provided another mechanism underlying the predictive ability of mTOR pathway mutation for ICI treatment response, because DNA repair pathways plays a role in TMB accumulation and neoantigen production, thus they were previously demonstrated to be associated with sensitivity of ICI treatment [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers

et al. 2022

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Background mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. Methods Using Memorial Sloan-Kettering Cancer Center dataset (MSKCC), we extracted mTOR pathway gene mutations for stepwise Cox regression in 1661 cancer patients received ICI. We associated the mutation of the gene signature resulted from the stepwise Cox regression with the 1661 patients’ survival. Other 553 ICI-treated patients were collected from 6 cohorts for validation. We also performed this survival association in patients without ICI treatment from MSKCC as discovery (n = 2244) and The Cancer Genome Atlas (TCGA) as validation (n = 763). Pathway enrichment analysis were performed using transcriptome profiles from TCGA and IMvigor210 trial to investigate the potential mechanism. Results We identified 8 genes involved in mTOR pathway, including FGFR2, PIK3C3, FGFR4, FGFR1, FGF3, AKT1, mTOR, and RPTOR, resulted from stepwise Cox regression in discovery (n = 1661). In both discovery (n = 1661) and validation (n = 553), the mutation of the 8-gene signature was associated with better survival of the patients treated with ICI, which was independent of tumor mutation burden (TMB) and mainly attributed to the missense mutations. This survival association was not observed in patients without ICI therapy. Intriguingly, the mutation of the 8-gene signature was associated with increased TMB and PD1/PD-L1 expression. Immunologically, pathways involved in anti-tumor immune response were enriched in presence of this mutational signature in mTOR pathway, leading to increased infiltration of immune effector cells (e.g., CD8 + T cells, NK cells, and M1 macrophages), but decreased infiltration of immune inhibitory M2 macrophages. Conclusions These results suggested that mTOR pathway gene mutations were predictive of better survival upon ICI treatment in multiple cancers, likely by its association with enhanced anti-tumor immunity. Larger studies are warranted to validate our findings.

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“…MTOR is a serine/threonine kinase that regulates cellular processes such as protein synthesis, metabolism, aging, regeneration, and autophagy ( MURUGAN, 2019 ). Over the past few decades, many studies have shown that mTOR is activated in various tumors, thereby the use of mTOR signaling pathways and mTOR inhibitors has received widespread attention ( HUA et al, 2019 ; DANESH PAZHOOH et al, 2021 ). Luo et al reported that erianin could inhibit the survival rate, and G 2 /M arrest and promote apoptosis in OSCC cells (WSU-HN4, SCC-9, and CAL-27 cells).…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Erianin: A phytoestrogen with therapeutic potential

Zhang

Liu

et al. 2023

Front. Pharmacol.

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Erianin, a phytoestrogen with therapeutic potential, is one of the major active components of Dendrobll caulis. Erianin has a variety of pharmacological effects, such as anti-tumor, anti-inflammatory, anti-diabetic retinopathy, anti-psoriasis, and antibacterial effects. Especially, in regard to the anti-tumor effect of erianin, the underlying molecular mechanism has been partly clarified. In fact, the numerous pharmacological actions of erianin are complex and interrelated, mainly including ERK1/2, PI3K/Akt, JAK2/STAT3, HIF-1α/PD-L1, PPT1/mTOR, JNK/c-Jun, and p38 MAPK signal pathway. However, on account of the poor water solubility and the low bioavailability of erianin, greatly affected and limited its further development and application. And it is worthwhile and meaningful to explore more extensive pharmacological effects and mechanisms, clarify pharmacokinetics, and synthesize the derivatives of erianin. Conclusively, in this paper, the pharmacological effects of erianin and its mechanism, pharmacokinetics, and derivatives studies were reviewed, in order to provide a reference for the development and application of erianin.

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mTOR pathway and DNA damage response: A therapeutic strategy in cancer therapy

Cited by 20 publications

References 158 publications

ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

ATR promotes mTORC1 activation via de novo cholesterol synthesis in p16-low cancer cells

mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers

Erianin: A phytoestrogen with therapeutic potential

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