The greedy nature of mutant RAS: a boon for drug discovery targeting cancer metabolism?
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.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Jing
J
Lv
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Jieqiong
J
Wang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Siyu
S
Chang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX 77030, USA mliu@ibt.tamhsc.edu xfpang@bio.ecnu.edu.cn.
Mingyao
M
Liu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China mliu@ibt.tamhsc.edu xfpang@bio.ecnu.edu.cn.
Xiufeng
X
Pang
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D005973:Glutamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
RAS; anabolic metabolism; bioenergetic metabolism; cancer metabolism; scavenging pathway