KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer

Abstract

Tumors driven by mutant KRAS are among the most aggressive and refractory to treatment. Unfortunately, despite the efforts, targeting alterations of this GTPase, either directly or by acting on the downstream signaling cascades, has been, so far, largely unsuccessful. However, recently, novel therapeutic opportunities are emerging based on the effect that this oncogenic lesion exerts in rewiring the cancer cell metabolism. Cancer cells that become dependent on KRAS-driven metabolic adaptations are sensitive to the inhibition of these metabolic routes, revealing novel therapeutic windows of intervention. In general, mutant KRAS fosters tumor growth by shifting cancer cell metabolism toward anabolic pathways. Depending on the tumor, KRAS-driven metabolic rewiring occurs by up-regulating rate-limiting enzymes involved in amino acid, fatty acid, or nucleotide biosynthesis, and by stimulating scavenging pathways such as macropinocytosis and autophagy, which, in turn, provide building blocks to the anabolic routes, also maintaining the energy levels and the cell redox potential ( 1 ). This review will discuss the most recent findings on mutant KRAS metabolic reliance in tumor models of pancreatic and non-small-cell lung cancer, also highlighting the role that these metabolic adaptations play in resistance to target therapy. The effects of constitutive KRAS activation in glycolysis elevation, amino acids metabolism reprogramming, fatty acid turnover, and nucleotide biosynthesis will be discussed also in the context of different genetic landscapes.

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

“…Many transporters and enzymes involve in glucose uptake and metabolism, e.g., glucose transporters (GLUTs), monocarboxylate transporters, hexokinase 2, lactate dehydrogenase A, and pyruvate dehydrogenase kinase 1, and transcription factors that regulate their expression, e.g., hypoxia inducible factor-1 alpha (HIF-1α) and c-myc, are overexpressed in various cancers [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Similarly, it is well-known that in various cancers, gene mutations and dysregulation occur in Kras/mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR, which are signal transduction pathways related to glycolysis control [ 26 , 43 ]. It is also known that the tumor suppressor gene p53 has a role in suppressing glycolysis by inhibiting GLUTs expression and phosphofructokinase activity [ 44 , 45 , 46 , 47 , 48 , 49 ], whereas mutant p53 conversely promotes glucose uptake and glycolysis [ 48 , 49 ].…”

“…Since glutamine plays an important role as a source of nitrogen in amino acids and nucleic acids, it is known that many cancer cells have a high dependence on glutamine [ 66 , 67 , 68 , 69 , 70 ]. Glutamine uptake and metabolism in cancer cells is regulated by PI3K, Kras, and c-myc [ 26 , 43 , 66 , 67 , 71 , 72 , 73 , 74 , 75 ]. Tryptophan is an important amino acid for the activation of immune cells, but cancer cells overexpress the tryptophan-metabolizing enzyme IDO, which suppresses immune cell function by depleting tryptophan in the tumor microenvironment [ 66 ].…”

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

“…Although transcriptome profiles are not associated with specific mutations, the frequency of KRAS mutation varies among the CRC subtypes (23% in CMS1, 28% in CMS2, 68% in CMS3, and 38% in CMS4), these data suggest mutations may drive distinct programs of metabolism gene expression [7]. Mutations in KRAS or BRAF genes appear to play an important role in the regulation of metabolic reprogramming in multiple cancers, including CRC [8][9][10][11]. In this study, two established and common prognostic biomarkers in CRC were investigated: KRAS and BRAF mutation status.…”

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

“…Additional alternatives based upon the biochemical and biological processes associated with KRAS activation are being investigated to impair its oncogenic activity. These encompass targeting post-translational modifications to interfere with KRAS subcellular localization and translocation to the membrane, hindering the metabolic adaptations and scavenging pathways (e.g., authophagy and micropinocytosis) used by mutant KRAS cells for energy production and nutrient uptake [10,[16][17][18][19]. In this regard, farnesyltransferase inhibitors were tested in the past as a strategy to limit KRAS translocation to the plasma membrane by impairing prenylation of the cysteine in the CAAX motif, the initial step of KRAS post-translational modifications.…”