Metabolic Dependencies in RAS-Driven Cancers - PubMed (original) (raw)

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Metabolic Dependencies in RAS-Driven Cancers

Alec C Kimmelman. Clin Cancer Res. 2015.

Abstract

The ability to inhibit the RAS oncogene has been the holy grail of oncology because of the critical role of this gene in a multitude of tumor types. In addition, RAS-mutant tumors are among the most aggressive and refractory to treatment. Although directly targeting the RAS oncogene has proven challenging, an alternative approach for treating RAS-driven cancers is to inhibit critical downstream events that are required for tumor maintenance. Indeed, much focus has been put on inhibiting signaling cascades downstream of RAS. Recent studies have shown that oncogenic RAS promotes a metabolic reprogramming of tumor cells, shifting them toward an anabolic metabolism necessary to produce biomass to support unconstrained proliferation. These cancers also use a diverse set of fuel sources to meet their metabolic needs and have even developed a variety of mechanisms to act as metabolic scavengers to obtain necessary metabolic substrates from both extracellular and intracellular sources. Collectively, these adaptations can create "metabolic bottlenecks" whereby tumor cells rely on particular pathways or rate-limiting metabolites. In this regard, inhibiting individual or combinations of these metabolic pathways can attenuate growth in preclinical models. Because these dependencies are tumor selective and downstream of oncogenic RAS, there is the opportunity for therapeutic intervention. Although targeting tumor metabolism is still in the early days of translation to patients, our continued advances in understanding critical metabolic adaptations in RAS-driven cancers, as well as the ability to study this altered metabolism in relevant tumor models, will accelerate the development of new therapeutic approaches. Clin Cancer Res; 21(8); 1828-34. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers."

©2015 American Association for Cancer Research.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

A.C. Kimmelman reports receiving speakers bureau honoraria from Agios and the US Oncology Network, and is a consultant/advisory board member for Astellas Pharma, FORMA Therapeutics, and Gilead. No other potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1

Metabolic scavenging pathways have critical roles in Ras-driven cancers. Autophagy can degrade intracellular cargo by sequestering it in autophagosomes. These fuse with lysosomes where the cargo is degraded and subsequently recycled back into the cytosol. Macropinocytosis is associated with membrane ruffling that can lead to the internalization of extracellular material such as albumin with subsequent lysosomal degradation. Both pathways can supply metabolic substrates for various metabolic pathways. Chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit lysosomal acidification and therefore block the degradation of cargo in both pathways. Ethylisopropylamiloride (EIPA) inhibits macropinocytosis.

Figure 2

Figure 2

Oncogenic Kras (KRAS*) can create metabolic alterations in pancreatic tumor cells. (A). Activation of the of the RAF/MEK/ERK cascade leads to increased MYC levels which promotes increased expression of various enzymes involved in glucose metabolism (representative enzymes that are increased are indicated). This promotes increased glycolysis as well as increased flux of glucose derived carbon through anabolic pathways such as the non-oxidative arm of the pentose phosphate pathway (PPP) to produce ribose for DNA/RNA biosynthesis and the hexosamine biosynthesis pathway (HBP) to produce glycosylation precursors. Kras regulated pathways are depicted in red and representative enzymes upregulated by oncogenic Kras are indicated for each pathway. The oxidative PPP (in purple) which can produce NADPH is not regulated by Kras. OAA (oxaloacetate); Asp (aspartate) (B). Kras causes a shift in glutamine metabolism in pancreatic cancers, through an unknown downstream program, repressing GLUD1 and increasing GOT1 expression. This pathway is a major source of cytosolic NADPH in Kras mutant pancreatic cancer cells and is critical for redox balance. Both mitochondrial (the structure depicted is a mitochondria) and cytosolic enzymes are involved in this pathway.

Figure 2

Figure 2

Oncogenic Kras (KRAS*) can create metabolic alterations in pancreatic tumor cells. (A). Activation of the of the RAF/MEK/ERK cascade leads to increased MYC levels which promotes increased expression of various enzymes involved in glucose metabolism (representative enzymes that are increased are indicated). This promotes increased glycolysis as well as increased flux of glucose derived carbon through anabolic pathways such as the non-oxidative arm of the pentose phosphate pathway (PPP) to produce ribose for DNA/RNA biosynthesis and the hexosamine biosynthesis pathway (HBP) to produce glycosylation precursors. Kras regulated pathways are depicted in red and representative enzymes upregulated by oncogenic Kras are indicated for each pathway. The oxidative PPP (in purple) which can produce NADPH is not regulated by Kras. OAA (oxaloacetate); Asp (aspartate) (B). Kras causes a shift in glutamine metabolism in pancreatic cancers, through an unknown downstream program, repressing GLUD1 and increasing GOT1 expression. This pathway is a major source of cytosolic NADPH in Kras mutant pancreatic cancer cells and is critical for redox balance. Both mitochondrial (the structure depicted is a mitochondria) and cytosolic enzymes are involved in this pathway.

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