The greedy nature of mutant RAS: a boon for drug discovery targeting cancer metabolism?

Abstract

RAS oncogene mutations are frequently detected in human cancers. Among RAS-mediated tumorigenesis, KRAS-driven cancers are the most frequently diagnosed and resistant to current therapies. Despite more than three decades of intensive efforts, there are still no specific therapies for mutant RAS proteins. While trying to block those well-established downstream pathways, such as the RAF-MAPK pathway and the PI3K-AKT pathway, attentions have been paid to potential effects of RAS on metabolic pathways and the feasibility for targeting these pathways. Recent studies have proved that RAS not only promotes aerobic glycolysis and glutamine metabolism reprograming to provide energy, but it also facilitates branched metabolism pathways, autophagy, and macropinocytosis. These alterations generate building blocks for tumor growth and strengthen antioxidant defense in tumor cells. All of these metabolic changes meet different demands of RAS-driven cancers, making them distinct from normal cells. Indeed, some achievements have been made to inhibit tumor growth through targeting specific metabolism rewiring in preclinical models. Although there is still a long way to elucidate the landscape of altered metabolism, we believe that specific metabolic enzymes or pathways could be therapeutically targeted for selective inhibition of RAS-driven cancers.

Clinical, environmental and histological distribution ofBRAF,NRASandTERTpromoter mutations among patients with cutaneous melanoma: a retrospective study of 563 patients*

“…The pronounced effect of NRAS mutations on survival, particularly in combination with TERT promoter mutations, can probably be attributed to its involvement in multiple pathways. Besides being upstream of the RAF–MAPK pathway, RAS also affects metabolic pathways and promotes aerobic glycolysis and glutamine metabolism to provide energy and facilitate autophagy and macropinocytosis, which generate building blocks for tumour growth and strengthen the antioxidant defence in tumour cells 17,31 . However, due to the dependence of TERT expression on RAS signalling in mutant tumours, targeting with the telomere‐uncapping agent 6‐thio‐2′‐deoxyguanosine in combination with the mitochondrial inhibitor gamitrinib has been shown to suppress NRAS ‐mutant melanoma effectively in cells and animal models 32 …”

Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma

“…KRAS mutations are frequently associated with a metabolic reprogramming, such as highly active glucose metabolism, differential channeling of glucose intermediates, reprogrammed glutamine metabolism, and increased autophagy and macropinocytosis (4,14). These changes are critical for utilization of nutrients to satisfy biosynthetic demands and maintain redox equilibrium for cell survival.…”

Oncogene-Driven Metabolic Alterations in Cancer

“…Numerous findings demonstrate the involvement of mutant KRAS in the metabolic rewiring of several types of human cancer ( Pylayeva-Gupta et al ., 2011 ; Kimmelman, 2015 ; Lv et al ., 2016 ; Kawada et al ., 2017 ; Kerr and Martins, 2017 ), including upregulation of glucose uptake, glutamine utilization, and aerobic glycolysis ( Onetti et al ., 1997 ; Ying et al ., 2012 ; Son et al ., 2013 ). Using patient-derived NSCLC tumors, cell lines, and animal models, several studies have consistently identified the influence of mutant KRAS on metabolic reprogramming in NSCLC.…”