Targeting MYC Dependence by Metabolic Inhibitors in Cancer

• Type of Material: Article
• Authors: Himalee Sabnis, Emory University; Ranganatha R. Somasagara, Emory University; Kevin Bunting, Emory University
• Language: English
• Date: 2017-04-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2017 by the authors; licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/genes8040114
• Title of Journal or Parent Work: Genes
• ISSN: 2073-4425
• Volume: 8
• Issue: 4
• Start Page: 114
• End Page: 114
• Grant/Funding Information: The authors acknowledge support through the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and Emory University School of Medicine.; The work was also supported by the National Institutes of Health, National Diabetes, Digestive, and Kidney Diseases Institute (R01DK059380).
• Keywords: metabolism; C-MYC; INDUCIBLE FACTOR-I; MTOR INHIBITOR; TUMOR METABOLISM; PYRUVATE-KINASE GENE; NEGATIVE BREAST-CANCER; combination therapy; transcription factor; Genetics & Heredity; LACTATE-DEHYDROGENASE; GLUCOSE-MEDIATED INDUCTION; ANTITUMOR-ACTIVITY; cancer; ACUTE MYELOID-LEUKEMIA; Science & Technology; Life Sciences & Biomedicine; signal transduction
• Research Categories: Health Sciences, Oncology

Abstract

MYC is a critical growth regulatory gene that is commonly over expressed in a wide range of cancers. Therapeutic targeting of MYC transcriptional activity has long been a goal, but it has been difficult to achieve with drugs that directly block its DNA-binding ability. Additional approaches that exploit oncogene addiction are promising strategies against MYC-driven cancers. Also, drugs that target metabolic regulatory pathways and enzymes have potential for indirectly reducing MYC levels. Glucose metabolism and oxidative phosphorylation, which can be targeted by multiple agents, promote cell growth and MYC expression. Likewise, modulation of the signaling pathways and protein synthesis regulated by adenosine monophosphate-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can also be an effective route for suppressing MYC translation. Furthermore, recent data suggest that metabolism of nucleotides, fatty acids and glutamine are exploited to alter MYC levels. Combination therapies offer potential new approaches to overcome metabolic plasticity caused by single agents. Although potential toxicities must be carefully controlled, new inhibitors currently being tested in clinical trials offer significant promise. Therefore, as both a downstream target of metabolism and an upstream regulator, MYC is a prominent central regulator of cancer metabolism. Exploiting metabolic vulnerabilities of MYC-driven cancers is an emerging research area with translational potential.