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Cited by 326Cancer, Hypoxia, and MetabolismProtein Kinase Regulation and GTPase SignalingMetabolism, Diabetes, and Cancer

The metabolic landscape of RAS-driven cancers from biology to therapy

Open access
Mukhopadhyay, Suman, Vander Heiden, Matthew G., McCormick, Frank·2021·Nature Cancer
DOI 10.1038/s43018-021-00184-xPMC PMC8045781
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Abstract

Our understanding of how the RAS protein family, and in particular mutant KRAS, promotes metabolic dysregulation in cancer cells has advanced substantially over the last decade. In this Review, we discuss the metabolic reprogramming mediated by oncogenic RAS in cancer and elucidate the underlying mechanisms that could translate to novel therapeutic opportunities to target metabolic vulnerabilities in RAS-driven cancers. Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.

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Written from the paper’s full text.

TL;DR

This review argues that oncogenic RAS, especially mutant KRAS, rewires glucose, glutamine, lipid, redox, and nutrient-scavenging metabolism to support tumor growth and therapy resistance. It surveys preclinical and early clinical strategies for exploiting these metabolic dependencies, while stressing that effective treatments will likely need to be context-specific and combinatorial.

Key findings

  • RAS mutations contribute to roughly one third of human cancers, with KRAS predominant in many adenocarcinomas, NRAS prominent in melanoma and myeloid cancers, and HRAS mutated less often but mainly in bladder and head/neck squamous carcinoma. Mutation patterns vary by tissue: about 22% of oncogenic lung adenocarcinoma mutations are KRAS, while nearly 24% of skin cutaneous melanoma mutations are NRAS; G12C dominates in lung adenocarcinoma and G12D in pancreatic adenocarcinoma.
  • Mutant KRAS increases glucose uptake and glycolytic flux through GLUT1, HK1/HK2, PFK1, ENO1, and LDHA, and also supports the hexosamine biosynthesis pathway and non-oxidative pentose phosphate pathway. KRAS4A can directly regulate HK1. Proposed glycolytic vulnerabilities include GAPDH inhibition by vitamin C, methylglyoxal scavengers combined with AKT inhibitors, and GLUT inhibitors such as silybin and BAY-876.
  • KRAS-driven tumors often depend on glutaminolysis, the GOT1/2–ME1 pathway, NRF2-driven antioxidant programs, and xCT/cysteine metabolism; glutaminase inhibition may be especially relevant in tumors with KEAP1 or LKB1 co-mutations, and cysteine depletion can trigger ferroptosis. Lipid-related targets include ACLY, ACSL3, FASN, and fatty acid oxidation, while nutrient scavenging involves autophagy, NIX-mediated mitophagy, and macropinocytosis, with allele-specific differences such as KRAS G12R being impaired in PI3K signaling and macropinocytosis.
  • Therapy resistance is linked to ROS management, stress granule formation via 15-d-PGJ2/NRF2, and compensatory signaling. KRAS G12C inhibitors show promise, but resistance suggests combinations with mTOR, SHP2, CDK4/6, or metabolic inhibitors; clinical trials are targeting glutaminolysis and autophagy.

Methods

  • Narrative review, not a primary experimental study; it synthesizes literature on RAS biology and cancer metabolism, focusing mainly on KRAS and noting other isoforms where known.
  • Mutation data for figures were compiled from AACR Genie Release 6.1-public, COSMIC v90, cBioPortal, TCGA, and NCI GDC; Figure 4 used previously published driver mutation data from ICGC/TCGA controlled access and an in-house pathway pattern extraction pipeline implemented in R.
  • No systematic review, meta-analysis, or new experimental data are reported.

Limitations

  • The authors state that many open questions remain: the interplay among KRAS isoforms, RAS alleles, tissue of origin, and metabolic alterations is poorly understood; whether RAS-mediated metabolic changes are common across all RAS-driven cancers is unanswered; and HRAS/NRAS metabolic landscapes are less explored.
  • The authors note that metabolic flexibility and compensatory pathways can limit single-pathway targeting, that toxicity to normal cells and immune cells is a major concern, and that in vivo glutamine dependencies can differ from cell-culture findings, making model choice important.
  • Evident from the text: as a review, it provides no primary validation or systematic search criteria, and many proposed metabolic therapies remain preclinical or early clinical and unapproved.

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Integrity signals

Registry

Crossref · 10.1038/s43018-021-00184-x

Cites

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Statistics

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Claims the paper makes

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  • Findingown data

    A survey of PanCancer Analysis of Whole Genomes Consortium samples against KEGG pathways reveals oncogenic driver genes participating in diverse metabolic processes in numerous cancer tissue types.

    “Analysis of data from the PanCancer Analysis of Whole Genomes Consortium samples135 on the KEGG pathway database137 depicts oncogenic driver genes involved in various metabolism processes in many cancer tissue types (Fig. 4a)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [135] ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020). source

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    • cites [137] Alam, H. et al. KMT2D deficiency impairs super-enhancers to confer a glycolytic vulnerability in lung cancer. Cancer Cell 37, 599–617 (2020). source

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  • Findingown data

    A gene-level examination of each pathway reveals driver genes that are co-altered across diverse tissue types.

    “with a gene-level analysis of each corresponding pathway unveiling driver genes that are co-altered in diverse tissue types (Fig. 4b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [135] ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020). source

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    • cites [137] Alam, H. et al. KMT2D deficiency impairs super-enhancers to confer a glycolytic vulnerability in lung cancer. Cancer Cell 37, 599–617 (2020). source

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  • Findingown data

    Network analysis connects oncogenic RAS to several mutated driver genes-KMT2D, PIK3CA, PTEN, and IDH1-that control signaling and metabolic pathways in KRAS-driven cancers.

    “Network analysis of the several driver mutation genes, including KMT2D138, PIK3CA139, PTEN140, and IDH1141, that regulate signaling and metabolic pathways in KRAS-driven cancers, connects them to oncogenic RAS (Fig 4c).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [138] Castellano, E. & Downward, J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2, 261–274 (2011). source

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    • cites [139] Nogueira, C. et al. Cooperative interactions of PTEN deficiency and RAS activation in melanoma metastasis. Oncogene 29, 6222–6232 (2010). source

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  • Premisecitation

    Mutated RAS remains predominantly in the active GTP-bound state because GTP hydrolysis by its GTPase domain and by GTPase-activating proteins is impaired.

    “When mutated, oncogenic RAS remains preferentially in the active GTP-bound state, whereas GTP hydrolysis by its GTPase function and enzymes such as GTPase-activating proteins, is compromised1,2.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017). source

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  • Premisecitation

    KRAS promotes the hexosamine biosynthesis pathway, which supplies precursors for lipid and protein glycosylation.

    “KRAS also promotes the hexosamine biosynthesis pathway (HBP), which provides precursors for lipid and protein glycosylation34, and the non-oxidative arm of the pentose phosphate pathway (PPP)28, which supplies ribose, the backbone for nucleic acid production35 (Fig 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Slawson, C., Copeland, R. J. & Hart, G. W. O-GlcNAc signaling: a metabolic link between diabetes and cancer? Trends Biochem. Sci. 35, 547–555 (2010). source

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    Premisecitation

    KRAS is one of the most frequently mutated oncogenes in cancer and is commonly linked to therapeutic resistance and poor prognosis.

    “KRAS in particular, is among the most frequently mutated oncogenes in cancer and is commonly associated with therapeutic resistance and poor prognosis1,5,6.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017). source

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    • cites [5] Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013). source

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    • cites [6] Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017). source

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    Premisecitation

    LKB1 activates AMPK and has been linked to serine metabolism and tumorigenesis.

    “Furthermore, the tumor suppressor LKB1, which activates the energy sensor and metabolic regulator AMPK, has been linked to serine metabolism and induction of tumorigenesis45.”
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    • cites [45] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016). source

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    Interpretationcitation

    Acquired resistance may limit the efficacy of KRAS G12C inhibitors, which suggests that combination therapies may be needed.

    “However, the initial enthusiasm has been somewhat tempered by work suggesting that acquired resistance may constrain the inhibitors’ efficacy, which indicates that combination therapies may be needed11–14.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Hata, A. N. & Shaw, A. T. Resistance looms for KRASG12C inhibitors. Nat. Med. 26, 169–170 (2020). source

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    • cites [13] Fedele, C. et al. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J. Exp. Med. https://doi.org/10.1084/jem.20201414 (2021). source

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    Premisecitation

    Oncogenic HRAS increases glycolytic rates including glucose uptake, indicating that increased aerobic glycolysis is essential for RAS-mutant tumors to match energy production with biosynthetic needs.

    “Additionally, oncogenic HRAS mediates enhanced glycolytic rates including increased glucose uptake, underscoring the fact that increased aerobic glycolysis is essential for RAS-mutant tumors to match energy production with the requirement for enhanced biosynthetic pathways39.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Lock, R. et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell 22, 165–178 (2011). source

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    Premisecitation

    Oncogenes including RAS can promote aerobic glycolysis and activate anabolic pathways.

    “The recognition that oncogenes, including RAS, can promote aerobic glycolysis, commonly known as the Warburg effect, and activate anabolic pathways 22,23, has increased efforts to understand the molecular underpinnings of altered metabolism in cancer24.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Nagarajan, A., Malvi, P. & Wajapeyee, N. Oncogene-directed alterations in cancer cell metabolism. Trends Cancer 2, 365–377 (2016). source

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    • cites [23] Levine, A. J. & Puzio-Kuter, A. M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330, 1340–1344 (2010). source

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    Premisecitation

    Silybin, a natural flavonoid and potent GLUT1/GLUT4 inhibitor, was effective in a phase 1 prostate cancer trial with asymptomatic liver toxicity.

    “A promising candidate is silybin, a natural flavonoid and potent inhibitor of GLUT1 and GLUT4, which was shown to be effective in phase 1 trial of prostate cancer with asymptotic liver toxicity as an adverse effect48.”
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    • cites [48] Flaig, T. W. et al. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest. New Drugs 25, 139–146 (2007). source

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    Premisecitation

    Oncogenic KRAS upregulates PFK1, ENO1, and LDHA, promoting glycolytic flux and production of intermediates that can enter anabolic pathways.

    “Oncogenic KRAS also upregulates expression of other key glycolytic enzymes, such as PFK1, ENO1, and LDHA28,31–33, thereby promoting glycolytic flux and enabling the production of glycolytic intermediates that can be shunted into other anabolic pathways (Fig 2).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [28] Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). source

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    • cites [31] Kole, H. K., Resnick, R. J., Van Doren, M. & Racker, E. Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts. Arch. Biochem. Biophys. 286, 586–590 (1991). source

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    • cites [33] Chun, S. Y. et al. Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes. Mol. Cancer 9, 293 (2010). source

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    Interpretationcitation

    LKB1 loss is prevalent in KRAS-mutant lung cancers, suggesting that oncogenic KRAS may upregulate one-carbon metabolism by undermining AMPK's inhibitory role in the folate cycle.

    “Of note, LKB1 loss is prevalent in KRAS mutant lung cancers46, indicating that oncogenic KRAS not only induces mTOR activity, but might also upregulate one-carbon metabolism by undermining AMPK’s inhibitory role in the folate cycle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Calles, A. et al. Immunohistochemical loss of LKB1 is a biomarker for more aggressive biology in KRAS-mutant lung adenocarcinoma. Clin. Cancer Res. 21, 2851–2860 (2015). source

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    Premisecitation

    Mutant KRAS induces folate cycle enzymes and aberrant mTOR activation, a regulator of serine synthesis and the folate cycle.

    “Mutant KRAS has also been implicated in the induction of enzymes involved in the folate cycle42 and the aberrant activation of mTOR, a key regulator for both serine synthesis and the folate cycle43,44.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation

    KRAS is mutated in many cancers, predominantly adenocarcinomas, while NRAS mutations are prominent in melanoma and myeloid cancer.

    “Overall, KRAS is mutated in many cancers (predominantly adenocarcinomas), whereas NRAS mutations are prominent in melanoma and myeloid cancer4,15,16 (Fig. 1).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012). source

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    Interpretationreasoning

    Treatment efficacy cannot be extrapolated from one RAS-driven cancer to another; therapeutic approaches must be tailored to the isoform, mutation, and tissue.

    “Consequently, treatment efficacy cannot be extrapolated from one RAS-driven cancer to another, but rather therapeutic approaches must be tailored to the isoform, mutation and tissue.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In lung adenocarcinoma, 22% of oncogenic mutations occur in KRAS, whereas in skin cutaneous melanoma nearly 24% occur in NRAS.

    “For instance, 22% of oncogenic mutations in lung adenocarcinoma (LUAD) occur in KRAS, whereas nearly 24% of such mutations in skin cutaneous melanoma occur in NRAS15 (Fig. 1b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020). source

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    Premisecitation

    Highly glycolytic RAS-mutant cells are vulnerable to GAPDH inhibition by vitamin C, providing a rationale for testing it in KRAS- or BRAF-mutant colorectal cancer preclinical models.

    “Highly glycolytic RAS-mutant cells have been found to be vulnerable to inhibition of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with Vitamin C, providing a mechanistic rationale for exploring the therapeutic use of this vitamin against KRAS or BRAF mutant colorectal cancer preclinical models 38.”
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    • cites [38] Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396 (2015). source

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    Premisecitation

    RAS mutations and the deregulated signaling they cause account for one third of all human cancers.

    “However, RAS mutations and the resulting deregulated signaling events are responsible for one third of all human cancers4 (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012). source

      Not checked in the free run.

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    Premisecitation

    Mutant KRAS upregulates GLUT1 to increase glucose uptake and induces HK1 and HK2 to increase glycolytic activity.

    “Gene expression and metabolic flux analyses have shown that it upregulates the expression of the GLUT1 glucose transporter to promote glucose uptake by cells, as well as inducing expression of hexokinase 1 and 2 (HK1 and HK2) rate-limiting enzymes of glycolysis, to increase glycolytic activity27–30 (Fig. 2a).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [27] Gaglio, D. et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol. Syst. Biol. 7, 523 (2011). source

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    • cites [28] Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). source

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    • cites [29] Amendola, C. R. et al. KRAS4A directly regulates hexokinase 1. Nature 576, 482–486 (2019). source

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    • cites [30] Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009). source

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    Premisecitation

    Methylglyoxal-mediated stress is involved in cancer progression and activates AKT signaling, suggesting that methylglyoxal scavengers may be more effective with AKT inhibitors in KRAS-mutant colorectal cancer cells.

    “Methylglyoxal-mediated stress was shown to be involved in cancer progression41 and to be a potent activator of AKT signaling, suggesting that utilizing methylglyoxal scavengers in KRAS mutant colorectal cancer cells might be more effective when combined with AKT inhibitors40.”
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    • cites [40] Bellier, J. et al. Methylglyoxal scavengers resensitize KRAS-mutated colorectal tumors to cetuximab. Cell Rep 30, 1400–1416 e1406 (2020). source

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    Premisecitation

    KRAS regulates these metabolic pathways through MAPK-dependent signaling, supporting survival and conferring a proliferative advantage on tumors.

    “KRAS regulates these pathways through MAPK-dependent signaling cascades, ultimately supporting cell survival and conferring a proliferative advantage on tumors28,36,37.”
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    • cites [28] Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). source

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    • cites [36] Taparra, K. et al. O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J. Clin. Invest. 128, 4924–4937 (2018). source

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    • cites [37] Santana-Codina, N. et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat. Commun. 9, 4945 (2018). source

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    Premisecitation

    Limiting glutamine use combined with chemotherapy halts pancreatic tumor growth in preclinical mouse models and is not toxic to normal cells.

    “Limiting glutamine use combined with chemotherapy is a viable means to halt pancreatic tumor growth in preclinical mouse models and is not toxic to normal cells58,60,65.”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    • cites [60] Mukhopadhyay, S. et al. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-19-1363 (2020). source

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    • cites [65] Saqcena, M. et al. Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs. Oncogene 34, 2672–2680 (2015). source

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    Premisecitation

    Lung tumor cells with oncogenic KRAS and loss-of-function KEAP1 mutations are more dependent on glutamine and more susceptible to glutaminase inhibition than other cells.

    “Cells from advanced lung tumors with oncogenic KRAS and loss-of-function KEAP1 mutations were more dependent on increased amounts of glutamine than other cells, making them more susceptible to glutaminase inhibition62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017). source

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    Premisecitation

    Oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression and constitutively activating NRF2-controlled genes to maintain redox balance and promote tumorigenesis.

    “In addition to activating the GOT2/GOT1/Malic Enzyme 1 (ME1) pathway, oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression59,60 and by constitutively activating the battery of genes controlled by NRF2 to maintain the redox balance and promote tumorigenesis61.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [59] DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011). source

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    • cites [60] Mukhopadhyay, S. et al. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-19-1363 (2020). source

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    • cites [61] Chio, I. I. C. et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166, 963–976 (2016). source

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    Premisecitation

    KRAS-driven lung adenocarcinomas with TP53 mutation induce immune cell production, while tumors with KEAP1 mutations rewire metabolism.

    “Moreover, KRAS-driven lung adenocarcinomas with TP53 mutation induce immune cell production, while tumors with KEAP1 mutations rewire metabolism71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Best, S. A. et al. Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma. Nat. Commun. 10, 4190 (2019). source

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    Premisecitation

    Concurrent KRAS and LKB1 mutations confer vulnerabilities in pancreatic cancer, but the mechanisms differ from those in lung cancer.

    “Concurrent mutations in KRAS and LKB1 also confer vulnerabilities in pancreatic cancer, but the mechanisms are different from those in lung cancer45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016). source

      Not checked in the free run.

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    Premisecitation

    Co-occurrence of mutant KRAS and LKB1 deficiency in lung cancer patients results in more aggressive tumors, higher metastasis frequency, and therapy resistance.

    “Co-occurrence of mutant KRAS and LKB1 deficiency in patients with lung cancer resulted in more aggressive tumors, higher frequency of metastasis, and therapy resistance67.”
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    • cites [67] Skoulidis, F. & Heymach, J. V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat. Rev. Cancer 19, 495–509 (2019). source

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    Premisecitation

    KRAS stimulates alanine aminotransferase activity, increasing alpha-ketoglutarate for the TCA cycle and mitochondrial ROS, which was required for mutant KRAS-driven lung tumorigenesis in mice.

    “However, KRAS has also been shown to promote cancer cell growth by stimulating alanine aminotransferase activity, leading to high levels of α-ketoglutarate for the TCA cycle and mitochondrial ROS generation, which was required for mutant KRAS-driven tumorigenesis in a mouse model of lung cancer64.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010). source

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    Premisecitation

    Multiple oncogenes drive the transcriptional reprogramming required for tumor cell proliferation, and many cancer driver genes also disrupt metabolism.

    “Several oncogenes coordinate the transcriptional reprogramming that tumor cells need to thrive, with many cancer driver genes also perturbing metabolism135,136.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [135] ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020). source

      Not checked in the free run.

    • cites [136] Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M. & Hirakawa, M. KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res. 38, D355–D360 (2010). source

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    Premisecitation

    KRAS-dependent upregulation of GOT1/2 in pancreatic cancer facilitates aspartate production for nucleotide biosynthesis and allows NADPH generation via ME1.

    “For instance, KRAS-dependent upregulation of Glutamate Oxaloacetate Transaminase 1,2. (GOT) expression in pancreatic cancer facilitates production of aspartate for nucleotide biosynthesis, and allows NADPH generation via ME157,58 (Fig 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013). source

      Not checked in the free run.

    • cites [58] Mukhopadhyay, S., Saqcena, M. & Foster, D. A. Synthetic lethality in KRas-driven cancer cells created by glutamine deprivation. Oncoscience 2, 807–808 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In KRAS-driven lung adenocarcinoma, LKB1 loss often induces KEAP1 activation and metabolic alterations that can be counteracted by NRF2 activation, maintaining redox homeostasis and fueling glutamine-dependent energy metabolism.

    “Moreover, in oncogenic-KRAS-driven lung adenocarcinoma, loss of LKB1 often induces KEAP1 activation69 and leads to metabolic alterations that could be counteracted by activation of NRF270, thereby maintaining redox homeostasis and fueling energy metabolism in a glutamine-dependent manner.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Kaufman, J. M. et al. LKB1 loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K–AKT. J. Thorac. Oncol. 9, 794–804 (2014). source

      Not checked in the free run.

    • cites [70] Li, F. et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell 27, 698–711 (2015). source

      Not checked in the free run.

27 of 27

  • The paper relies on this without support.

    Metabolic changes caused by oncogenes can be broad, with several pathways altered at once within one cancer type.

    “Oncogene-directed metabolic alterations can have extensive impact, with multiple metabolic pathways being altered simultaneously in a single cancer type.”

  • The paper relies on this without support.

    Metabolic phenotypes differ between tumor types and also vary among tumors of the same type.

    “The elucidation of these events should also take into account the fact that metabolic phenotype is not uniform across different tumor types, and variability also exists between different tumors of the same type.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The identity of the amino acid imported by xCT changes

    Minor

    The paper calls xCT a cystine/glutamate antiporter and later describes cystine import, but the intervening description says xCT imports cysteine. These statements give different identities for the imported amino acid.

1 of 1

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Authors
Mukhopadhyay, S., Vander Heiden, M. G., & McCormick, F.
Affiliations
  • NYU Langone Health (US)
  • University of California, San Francisco (US)
Corresponding author
McCormick, Frank
ORCID
Venue
Nature Cancer
Publisher
Springer Science and Business Media LLC
Published
2021-03-24
Volume
2
Issue
3
Pages
271-283
ISSN
2662-1347 (ISSN-L)
DOI
10.1038/s43018-021-00184-x
PMC
PMC8045781
OpenAlex
W3138007187
Semantic Scholar
8d6bdc24577b7bfea70417686ccb3aa45bcc6c18
Cited by
315
References
158
Citations by year
2026: 27 · 2025: 48 · 2024: 81 · 2023: 73 · 2022: 56 · 2021: 30
FWCI
7.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
Funders
Frederick National Laboratory for Cancer Research (HHSN261200800001E)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
RAS-driven cancers, KRAS mutation, oncogenic Ras, tumor metabolic reprogramming, cancer metabolism, metabolic vulnerability, metabolic cancer therapy, Ras signaling
MeSH terms
Biology, Humans, Neoplasms, Genes, ras, ras Proteins

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

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