Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells

Brunelli, Laura; Caiola, Elisa; Marabese, Mirko; Broggini, Massimo; Pastorelli, Roberta

doi:10.18632/oncotarget.1958

Cited by 81 publications

(97 citation statements)

References 30 publications

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“…However, different KRAS mutations can have different effects; for instance, lung cancer cells harboring a KRAS-G12V mutation were much less glutamine dependent than those harboring G12C or G12D mutations, though the reasons for this were not clear 158 . In addition to inducing dependence on glutamine driven nucleotide metabolism 119 , mutant KRAS can increase dependence on aminotransferases through downregulation of GLUD, and drive increased production of NADPH to regenerate reduced glutathione and control ROS levels 34 ( Figure 5).…”

Section: Oncogenes and Glutamine Metabolismmentioning

confidence: 99%

“…Upregulates glutamine metabolism enzymes and transporters 6,31,48,145,177 KRAS mutations Drives dependence on glutamine metabolism, suppresses GLUD, and drives NADPH via malic enzyme 1 (ME1) 34,108,119,157,158 HIF1α or HIF2α stabilization Drives reductive carboxylation of glutamine to citrate for lipid production [89][90][91] HER2 upregulation Activates glutamine metabolism through MYC and NF-κB 156,220 p53, p63, or p73 activity Activates GLS2 expression 55,56,62,63 JAK2-V617F mutation Activates GLS and increases glutamine metabolism 221 mTOR upregulation Promotes glutamine metabolism via induction of MYC 155 and GLUD 69,73 or aminotransferases 117 NRF2 activation Promotes production of glutathione from glutamine 222 TGFβ-WNT upregulation Promotes SNAIL and DLX2 activation, which upregulate GLS and activates epithelial-mesenchymal transition 183 PKC zeta loss Stimulates glutamine metabolism through serine synthesis 223 …”

Section: Oncogenic Change Role In Glutamine Metabolismmentioning

confidence: 99%

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Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

248

136

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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Section: Oncogenes and Glutamine Metabolismmentioning

confidence: 99%

Section: Oncogenic Change Role In Glutamine Metabolismmentioning

confidence: 99%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

248

136

View full text Add to dashboard Cite

show abstract

“…Tracing by [ 13 C 2 -1,2]Glc shows that oncogenic KRAS increases flux into the PPP, presumably to fuel nucleotide biosynthesis (21,66). KRAS-driven cancer cells also require Gln for proliferation, although this requirement depends largely on extracellular environment (53) or specific mutation (67). Oncogenic KRAS increases production of [ 13 C 4 ]aspartate from [ 13 C 5 ]Gln (65), which can be transported into the cytoplasm and converted to OAA via cytosolic aspartate transaminase (68).…”

Section: Rasmentioning

confidence: 99%

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.Metabolism is the collection of predominantly enzyme-catalyzed biochemical transformations that meet the growth and survival demands of an organism. For nearly a century, scientists have documented profound metabolic changes that occur in tumors (1, 2). One of the earliest insights into cancer metabolism came when Otto Warburg noted increased uptake and fermentation of glucose (Glc) 3 to lactate in tumors relative to surrounding tissue, even in the presence of ample oxygen (2). Clinical cancer diagnosis exploits this "Warburg effect" by measuring uptake of the Glc analogue 18 F-deoxyglucose using positron emission tomography (PET), as the metabolic demands of differentiated, non-proliferating tissues generally require far less Glc than tumors (3).Oncoproteins and tumor suppressors are well-established regulators of metabolism, and mutations or dysregulated expression can lead to the altered metabolic phenotypes observed in many cancers (4, 5). Inactivating mutations in enzymes such as fumarate hydratase (FH) or succinate dehydrogenase (SDH) induce pathophysiological accumulation of substrates that inhibit other critical enzyme functions, whereas less common gain-of-function mutations such as in isocitrate dehydrogenases (IDH) produce metabolites that directly deregulate cellular processes (6). Additionally, cancer cells frequently express fetal isoforms of metabolic enzymes that are subject to different regulatory mechanisms to provide growth advantages (7). Gaining a systematic understanding of the metabolic changes that occur during carcinogenesis can thus be exploited for therapeutic and diagnostic purposes.Stable isotope-resolved metabolomics (SIRM) is a powerful approach developed by others and by us where isotopically enriched precursors such as [ 13 C 6 ]Glc are administered to a biological system, and the ensuing metabolic transformations are determined using appropriate analytic techniques to enable robust reconstruction of metabolic pathways (8 -11). Stable isotopes are non-radioactive and in SIRM practice are identical chemically and functionally to the most abundant isotope of that element. Incorporating stable isotopes such as 2 H, 13 C, or 15 N into biological precursors has long been used to trace their metabolism in living systems (12). SIRM is thus distinct from non-tracer-based metabolomics profiling for statistical models. Here, we review SIRM applications and demonstrate h...

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“…Non-small cell lung cancers (NSCLC) represent 85% of all lung cancers and generally present at advanced stages, requiring intensive multimodal therapy. Despite these medical interventions, 5-year survival rates are less than 5% (2). With the advancement in understanding about activating mutations in NSCLCs, many treatments have been developed with success against the array of different mutations identified in NSCLCs, such as EGFR, ALK, etc (3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo

Tao

Blanc

Wang

et al. 2016

Clinical Cancer Research

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Purpose: To investigate the potential roles that p16 (CDKN2A) and RB activation have in sensitization to MEK inhibitor in resistant KRAS-mutant non-small cell lung cancer cells (NSCLC) in vitro and in vivo.Experimental Design: Cell viability was measured with MTS assays. Effects of administration of radiation and combination drug treatments were evaluated by clonogenic assay, flow cytometry, and Western blots. DNA repair was assessed using immunofluorescent analysis. Finally, lung cancer xenografts were used to examine in vivo effects of drug treatment and radiation therapy.Results: In this study, we showed that sensitivity to MEK inhibitor correlated to the RB/p16/CDK4 pathway and knockdown of RB induced resistance in cell lines sensitive to MEK inhibitor. Also, overexpression of p16 and inhibition of CDK4 had the ability to sensitize normally resistant cell lines. Our data indicated that the MEK inhibitor (trametinib, GSK112012) cooperated with the CDK4/6 inhibitor (palbociclib, PD0332991) to strongly reduce cell viability of KRAS-mutant NSCLCs that were resistant to the MEK inhibitor in vitro and in vivo. In addition, we report for the first time that resistance of KRAS-mutant NSCLCs to MEK inhibitor is, at least partly, due to p16 mutation status, and we described a drug combination that efficiently reactivates the RB tumor suppressor pathway to trigger radiosensitizing effects, apoptosis, and cell-cycle arrest.Conclusions: Our findings suggest that MEK inhibitor in combination with CDK4/6 inhibitor has significant anti-KRASmutant NSCLC activity and radiosensitizing effect in preclinical models, potentially providing a novel therapeutic strategy for patients with advanced KRAS-mutant NSCLCs.

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Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells

Cited by 81 publications

References 30 publications

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo

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