Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma

Best, Sarah A.; Ding, Sheryl; Kersbergen, Ariena; Dong, Xueyi; Song, Ji‐Ying; Xie, Yi; Reljić, Boris; Li, Kaiming; Vince, James E.; Rathi, Vivek; Wright, Gavin; Ritchie, Matthew E.; Sutherland, Kate D.

doi:10.1038/s41467-019-12164-y

Cited by 74 publications

(80 citation statements)

References 70 publications

(110 reference statements)

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“…Hence, blocking G6PD could have potent anti-tumor effects by preventing nucleotide synthesis as well as impairing redox balance. The G6PD competitive inhibitor, 6-aminonicotinamide (6-AN) is being used to target cancer cells with increased PPP activity and has shown antineoplastic effects [150,151]. Downregulating G6PD expression has been shown to decrease cell viability of bladder cancer cell lines due to accumulation of ROS [149].…”

Section: Pentose Phosphate Pathway and Nucleotide Synthesismentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

154

115

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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Section: Pentose Phosphate Pathway and Nucleotide Synthesismentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

154

115

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“…In addition to orchestrating an antioxidant response to oxidative insults, there are emerging roles of NRF2 in promoting metabolic processes, including NADPH production [ 17 , 25 , 26 , 27 ], and the metabolism of lipids [ 27 , 28 , 29 , 30 , 31 ], amino acids (cysteine [ 19 , 32 ], glutamine [ 13 , 33 ], serine/glycine [ 12 , 34 ], asparagine [ 35 ]), nucleotides [ 25 , 36 ], and iron/heme [ 18 , 27 , 37 , 38 , 39 ], as outlined in Figure 2 a,b. Although these processes play an important role in supporting the antioxidant response in healthy cells, they are hijacked by cancer cells to support proliferation and survival [ 40 ], warranting further investigation into the relationship between NRF2 and metabolism in tumorigenesis.…”

Section: Modulation Of Metabolic Processes By Nrf2mentioning

confidence: 99%

“…Supportingly, Mitsuishi et al found that silencing the PPP enzymes G6PD or TKT reduced tumor growth in a KEAP1 mutant NSCLC xenograft model in a similar manner to silencing NRF2 [ 25 ]. Moreover, Best et al observed that Keap1 mutant mouse lung tumors expressed high levels of Taldo1 and were more sensitive to inhibition of the PPP enzyme Pgd with 6-AN compared with their wild-type counterparts [ 17 ]. Collectively, these studies highlight the regulation of the PPP by NRF2, which represents a critical metabolic vulnerability in vivo.…”

Section: Modulation Of Metabolic Processes By Nrf2mentioning

confidence: 99%

“…The roles of NRF2 in tumorigenesis are context-dependent [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ], and likely influenced by different aspects of metabolism. The role of ROS metabolism is better defined, however, and has been well-characterized during cancer initiation, progression, and metastasis [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

DeBlasi

DeNicola

2020

Cancers

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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

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“…Intriguingly, the activity of OGT inhibition has also been associated with NRF2dependent stress response, while OGT inhibition is known to facilitate NRF2 activation (Tan et al, 2017). Recent data have also validated that kelch like ECH associated protein 1 (KEAP1) is an inverse regulator of the antioxidant response transcription factor NRF2 (Best et al, 2019), whereas KEAP1 can also serve as a direct substrate of OGT (Chen et al, 2017b). The KEAP1/NRF2 axis can mediate responses of VSMCs to oxidative stress in high phosphate-induced calcification, and specifically, small interfering RNA (siRNA)-mediated knockdown of NRF2 and P62 can augment levels of reactive oxygen species and calcium deposition in VSMCs (Wei et al, 2019).…”

Section: Introductionmentioning

confidence: 98%

OGT-Mediated KEAP1 Glycosylation Accelerates NRF2 Degradation Leading to High Phosphate-Induced Vascular Calcification in Chronic Kidney Disease

Sheng

et al. 2020

Front. Physiol.

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Unraveling the complex regulatory pathways that mediate the effects of phosphate on vascular smooth muscle cells (VSMCs) may provide novel targets and therapies to limit the destructive effects of vascular calcification (VC) in patients with chronic kidney disease (CKD). Our previous studies have highlighted several signaling networks associated with VSMC autophagy, but the underlying mechanisms remain poorly understood. Thereafter, the current study was performed to characterize the functional relevance of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) in high phosphate-induced VC in CKD settings. We generated VC models in 5/6 nephrectomized rats in vivo and VSMC calcification models in vitro. Artificial modulation of OGT (knockdown and overexpression) was performed to explore the role of OGT in VSMC autophagy and VC in thoracic aorta, and in vivo experiments were used to substantiate in vitro findings. Mechanistically, co-immunoprecipitation (Co-IP) assay was performed to examine interaction between OGT and kelch like ECH associated protein 1 (KEAP1), and in vivo ubiquitination assay was performed to examine ubiquitination extent of nuclear factor erythroid 2-related factor 2 (NRF2). OGT was highly expressed in high phosphate-induced 5/6 nephrectomized rats and VSMCs. OGT silencing was shown to suppress high phosphate-induced calcification of VSMCs. OGT enhances KEAP1 glycosylation and thereby results in degradation and ubiquitination of NRF2, concurrently inhibiting VSMC autophagy to promote VSMC calcification in 5/6 nephrectomized rats. OGT inhibits VSMC autophagy through the KEAP1/NRF2 axis and thus accelerates high phosphate-induced VC in CKD.

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Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma

Cited by 74 publications

References 70 publications

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

OGT-Mediated KEAP1 Glycosylation Accelerates NRF2 Degradation Leading to High Phosphate-Induced Vascular Calcification in Chronic Kidney Disease

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