mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability

Gremke, Niklas; Polo, Pierfrancesco; Dort, Aaron; Schneikert, Jean; Elmshäuser, Sabrina; Brehm, Corinna U.; Klingmüller, Ursula; Schmitt, Anna; Reinhardt, Hans Christian; Timofeev, Oleg; Wanzel, Michael; Stiewe, Thorsten

doi:10.1038/s41467-020-18504-7

Cited by 108 publications

(83 citation statements)

References 86 publications

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“…Up-regulation of autophagy during cancer treatment can promote the survival or death of tumor cells. Although little is known about the role of autophagy in cancer therapy to date, recent studies suggest that autophagy therapy will become a new approach to lung cancer treatment [29][30][31]. For one thing, autophagy as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

Construction of a Prognostic Signature of Autophagy-Related lncRNAs in Non-Small Cell Lung Cancer

Zhang

Cao

Chen

2021

Preprint

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Background: Autophagy inhibits tumorigenesis by limiting inflammation, LncRNA regulates gene expression levels in the form of RNA at various levels, so both of them are closely related to the occurrence and development of tumors.Methods: 232 autophagy-related genes were used to construct a co-expression network to extract autophagy-related lncRNAs. A prognostic signature was constructed by multivariate regression analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) was applied to analyze pathway enrichment in cancer pathways. Immunoinfiltration analysis was used to analyze the relationship between the prognostic model and the tumor.Results: Nine autophagy-related lncRNAs were used to construct a prognostic model for non-small cell lung cancer. The median value of the value at risk was used to distinguish between the high and low risk groups, and the low-risk group had better survival. Because the KEGG pathway analysis showed that the prognostic model was enriched in some immune pathways, further exploration of immune infiltration was conducted and it was found that the prognostic model did play a unique role in the immune microenvironment. And the prognostic model was associated with clinical factors.Conclusion: The prognostic model of autophagy-related lncRNAs constructed by us can predict the prognosis of non-small cell lung cancer.

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Section: Discussionmentioning

confidence: 99%

Construction of a Prognostic Signature of Autophagy-Related lncRNAs in Non-Small Cell Lung Cancer

Zhang

Cao

Chen

2021

Preprint

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“…Recently, the tumor resistance to several antitumor agents (e.g. cisplatin, oxaliplatin, carboplatin, doxorubicin, etoposide, rapamycin, everolimus, alpelisib, pictilisib, and AZD8055) was related to elevated and sustained activation of the PI3K/mTOR signaling pathway ( 148 ). Curiously, in these PI3K/mTOR-activated cells, the promotion of energy metabolism stress (e.g.…”

Section: Pdt-mediated Autophagy Regulation In Tumor Cellsmentioning

confidence: 99%

“…Curiously, in these PI3K/mTOR-activated cells, the promotion of energy metabolism stress (e.g. 2-DG/DCA) led to apoptosis due to the sustained blockage of the pro-survival autophagy ( 148 ). Hence, photo-damaging organelles, such as mitochondria, lysosomes, or reticulum endoplasmic seem to be amenable to mediate death in drug-unresponsive tumors.…”

Section: Pdt-mediated Autophagy Regulation In Tumor Cellsmentioning

confidence: 99%

Autophagy Regulation and Photodynamic Therapy: Insights to Improve Outcomes of Cancer Treatment

et al. 2021

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Cancer is considered an age-related disease that, over the next 10 years, will become the most prevalent health problem worldwide. Although cancer therapy has remarkably improved in the last few decades, novel treatment concepts are needed to defeat this disease. Photodynamic Therapy (PDT) signalize a pathway to treat and manage several types of cancer. Over the past three decades, new light sources and photosensitizers (PS) have been developed to be applied in PDT. Nevertheless, there is a lack of knowledge to explain the main biochemical routes needed to trigger regulated cell death mechanisms, affecting, considerably, the scope of the PDT. Although autophagy modulation is being raised as an interesting strategy to be used in cancer therapy, the main aspects referring to the autophagy role over cell succumbing PDT-photoinduced damage remain elusive. Several reports emphasize cytoprotective autophagy, as an ultimate attempt of cells to cope with the photo-induced stress and to survive. Moreover, other underlying molecular mechanisms that evoke PDT-resistance of tumor cells were considered. We reviewed the paradigm about the PDT-regulated cell death mechanisms that involve autophagic impairment or boosted activation. To comprise the autophagy-targeted PDT-protocols to treat cancer, it was underlined those that alleviate or intensify PDT-resistance of tumor cells. Thereby, this review provides insights into the mechanisms by which PDT can be used to modulate autophagy and emphasizes how this field represents a promising therapeutic strategy for cancer treatment.

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“…However, in response to cellular stress (including treatment induced damage) the balance tips, and can elicit a pro-apoptotic response [105]. Indeed, upregulation of mTOR signalling has been demonstrated to promote resistance to anti-cancer therapies by enabling escape from cell death [111]. Interestingly, a number of strategies targeting mTOR and apoptotic priming concurrently have shown promise in improving anti-cancer therapeutic responses [112,113] to tip the balance of BH3 signalling towards a pro-apoptotic phenotype.…”

Section: Adaptations To Cellular Stress Prevent Metabolic Catastrophe and Deathmentioning

confidence: 99%

Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

McCann¹,

Kerr²

2021

Cancers

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Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.

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mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability

Cited by 108 publications

References 86 publications

Construction of a Prognostic Signature of Autophagy-Related lncRNAs in Non-Small Cell Lung Cancer

Construction of a Prognostic Signature of Autophagy-Related lncRNAs in Non-Small Cell Lung Cancer

Autophagy Regulation and Photodynamic Therapy: Insights to Improve Outcomes of Cancer Treatment

Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

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