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Targeting metabolic reprogramming in KRAS-driven cancers

International Journal of Clinical Oncology volume 22, pages 651–659 (2017)Cite this article

Abstract

Mutations of KRAS are found in a variety of human malignancies, including in pancreatic cancer, colorectal cancer, and non-small cell lung cancer at high frequency. To date, no effective treatments that target mutant variants of KRAS have been introduced into clinical practice. In recent years, a number of studies have shown that the oncogene KRAS plays a critical role in controlling cancer metabolism by orchestrating multiple metabolic changes. One of the metabolic hallmarks of malignant tumor cells is their dependency on aerobic glycolysis, known as the Warburg effect. The role of KRAS signaling in the regulation of aerobic glycolysis has been reported in several types of cancer. KRAS-driven cancers are characterized by altered metabolic pathways involving enhanced nutrients uptake, enhanced glycolysis, enhanced glutaminolysis, and elevated synthesis of fatty acids and nucleotides. However, Just how mutated KRAS can coordinate the metabolic shift to promote tumor growth and whether specific metabolic pathways are essential for the tumorigenesis of KRAS-driven cancers are questions which remain to be answered. In this context, the aim of this review is to summarize current data on KRAS-related metabolic alterations in cancer cells. Given that cancer cells rely on changes in metabolism to support their growth and survival, the targeting of metabolic processes may be a potential strategy for treating KRAS-driven cancers.

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Fig. 1

Abbreviations

ACS:

Acyl-CoA synthetase

ASNS:

Asparagine synthetase

BCAA:

Branched-chain amino acid

CMS:

Consensus molecular subtype

CRC:

Colorectal cancer

EGFR:

Epidermal growth factor receptor

FA:

Fatty acid

FASN:

Fatty acid synthase

FDG:

Fluorodeoxyglucose

FGFR:

Fibroblast growth factor receptor

GLS:

Glutaminase

GLUD1:

Glutamate dehydrogenase 1

GLUT1:

Glucose transporter-1

GOT:

Glutamate–oxaloacetate transaminase

HBP:

Hexosamine biosynthesis pathway

HK:

Hexokinase

MDH1:

Malate dehydrogenase 1

mTOR:

Mammalian target of rapamycin

NSCLC:

Non-small cell lung cancer

PDCA:

Pancreatic ductal cell carcinoma

PET:

Positron emission tomography

PKM2:

Pyruvate kinase M2

PPP:

Pentose phosphate pathway

ROS:

Reactive oxygen species

TCA:

Tricarboxylic acid

UPR:

Unfolded protein response

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Affiliations

  1. Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Kenji Kawada, Kosuke Toda & Yoshiharu Sakai

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  1. Kenji Kawada
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  2. Kosuke Toda
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  3. Yoshiharu Sakai
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Correspondence to Kenji Kawada.

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Kawada, K., Toda, K. & Sakai, Y. Targeting metabolic reprogramming in KRAS-driven cancers. Int J Clin Oncol 22, 651–659 (2017). https://doi.org/10.1007/s10147-017-1156-4

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  • DOI: https://doi.org/10.1007/s10147-017-1156-4

Keywords

  • KRAS
  • Cancer metabolism
  • Reprograming
  • Glycolysis
  • Glutaminolysis