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

In the paper

“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).”

What the sources say

• Partly supported

  The Results report increased glucose uptake and lactate production in K-Ras-transformed mouse fibroblasts, supporting increased glycolytic activity. They do not establish that GLUT1 or HK2 expression caused these changes; the transcriptional-profiling Results instead report lower Hk1 expression in transformed mouse fibroblasts, although a separate human-cell comparison found higher Hk1 expression than in normal breast tissue. No page numbers are provided in our copy. (LLM, conf=0.87)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The “Kras G12D Enhances Glycolytic Flux” section (p. 5) reports that Kras extinction reduced Glut1, Hk1, and Hk2 expression, glucose uptake, and lactate production. It concludes that oncogenic Kras G12D enhances glycolytic flux in the PDAC model, supporting the claim in that setting. (LLM, conf=0.94)

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

  The ‘KRAS4A enhances glycolytic flux’ section reports increased glucose consumption and glycolytic activity with oncogenic KRAS. It does not identify GLUT1 as the cause, and it explicitly reports that none of the tested KRAS proteins increased HK1 or HK2 levels; the observed HK1 effect involved regulation of its activity, not induced expression. (LLM, conf=0.90)

  cites [29] Amendola, C. R. et al. KRAS4A directly regulates hexokinase 1. Nature 576, 482–486 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The supplied passages (section labelled Abstract; page unavailable) report that mutant KRAS or BRAF cells had higher GLUT1 expression, glucose uptake, and glycolysis. Our copy does not report that mutant KRAS induces HK1 or HK2 expression; the search found only a reference to hexokinase as a drug target. That mechanism is therefore unsupported by this source. (LLM, conf=0.88)

  cites [30] Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  The main text (page not provided) says that limiting glutamine use makes KRas-driven cancer cells vulnerable to capecitabine and paclitaxel, supporting the combination-treatment concept. It does not report halted pancreatic tumor growth in mouse models or establish that the treatment is nontoxic to normal cells. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that CB-839 plus gemcitabine caused tumor regression in several mouse models without observed adverse events or marked body-weight changes. It also reports that glutamine restriction plus gemcitabine produced a synthetic-lethal effect in cancer cells but not in non-cancerous cells in culture. These findings do not establish the broader claim that the combination is not toxic to normal cells. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion section (page unavailable) reports that glutamine deprivation combined with capecitabine or paclitaxel increased nonviable PANC-1 pancreatic cancer cells, supporting the combination’s effect in a cell line. It does not report halted pancreatic tumor growth in mice or establish that the combination is nontoxic to normal cells; the comparison cells in the drug experiment were K-Ras wild-type cancer cell lines. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured

In the paper

“KRAS in particular, is among the most frequently mutated oncogenes in cancer and is commonly associated with therapeutic resistance and poor prognosis1,5,6.”

What the sources say

• Not checked yetcites [1] Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017). source
• Not checked yetcites [5] Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013). source
• Not checked yetcites [6] Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017). source

In the paper

“Furthermore, the tumor suppressor LKB1, which activates the energy sensor and metabolic regulator AMPK, has been linked to serine metabolism and induction of tumorigenesis45.”

What the sources say

• Not checked yetcites [45] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [11] Hata, A. N. & Shaw, A. T. Resistance looms for KRASG12C inhibitors. Nat. Med. 26, 169–170 (2020). source
• Not checked yetcites [12] Bar-Sagi, D., Knelson, E. H. & Sequist, L. V. A bright future for KRAS inhibitors. Nat. Cancer 1, 25–27 (2020). source
• Not checked yetcites [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
• Not checked yetcites [14] Ryan, M. B. et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin. Cancer Res. 26, 1633–1643 (2020). source

In the paper

“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.”

What the sources say

• Not checked yetcites [39] Lock, R. et al. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell 22, 165–178 (2011). source

In the paper

“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.”

What the sources say

• Not checked yetcites [22] Nagarajan, A., Malvi, P. & Wajapeyee, N. Oncogene-directed alterations in cancer cell metabolism. Trends Cancer 2, 365–377 (2016). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [28] Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). source
• Not checked yetcites [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
• Not checked yetcites [32] Racker, E., Resnick, R. J. & Feldman, R. Glycolysis and methylaminoisobutyrate uptake in rat-1 cells transfected with ras or myc oncogenes. Proc. Natl Acad. Sci. USA 82, 3535–3538 (1985). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [42] Moran, D. M. et al. KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol. Cancer Ther. 13, 1611–1624 (2014). source
• Not checked yetcites [43] Gomes, A. P. & Blenis, J. A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways. Curr. Opin. Biotechnol. 34, 110–117 (2015). source
• Not checked yetcites [44] Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016). source

In the paper

“Overall, KRAS is mutated in many cancers (predominantly adenocarcinomas), whereas NRAS mutations are prominent in melanoma and myeloid cancer4,15,16 (Fig. 1).”

What the sources say

• Not checked yetcites [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 yetcites [15] Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020). source
• Not checked yetcites [16] Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 (2020). source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [15] Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“However, RAS mutations and the resulting deregulated signaling events are responsible for one third of all human cancers4 (Figure 1).”

What the sources say

• Not checked yetcites [4] Prior, I. A., Lewis, P. D. & Mattos, C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 72, 2457–2467 (2012). source

In the paper

“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.”

What the sources say

• Not checked yetcites [40] Bellier, J. et al. Methylglyoxal scavengers resensitize KRAS-mutated colorectal tumors to cetuximab. Cell Rep 30, 1400–1416 e1406 (2020). source
• Not checked yetcites [41] Bellahcene, A., Nokin, M. J., Castronovo, V. & Schalkwijk, C. Methylglyoxal-derived stress: an emerging biological factor involved in the onset and progression of cancer. Semin. Cancer Biol. 49, 64–74 (2018). source

In the paper

“KRAS regulates these pathways through MAPK-dependent signaling cascades, ultimately supporting cell survival and conferring a proliferative advantage on tumors28,36,37.”

What the sources say

• Not checked yetcites [28] Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012). source
• Not checked yetcites [36] Taparra, K. et al. O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J. Clin. Invest. 128, 4924–4937 (2018). source
• Not checked yetcites [37] Santana-Codina, N. et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nat. Commun. 9, 4945 (2018). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [59] DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011). source
• Not checked yetcites [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
• Not checked yetcites [61] Chio, I. I. C. et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166, 963–976 (2016). source

In the paper

“Moreover, KRAS-driven lung adenocarcinomas with TP53 mutation induce immune cell production, while tumors with KEAP1 mutations rewire metabolism71.”

What the sources say

• Not checked yetcites [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

In the paper

“Concurrent mutations in KRAS and LKB1 also confer vulnerabilities in pancreatic cancer, but the mechanisms are different from those in lung cancer45.”

What the sources say

• Not checked yetcites [45] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Several oncogenes coordinate the transcriptional reprogramming that tumor cells need to thrive, with many cancer driver genes also perturbing metabolism135,136.”

What the sources say

• Not checked yetcites [135] ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020). source
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [57] Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013). source
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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