Targeting MYC Dependence by Metabolic Inhibitors in Cancer

Abstract:MYC is a critical growth regulatory gene that is commonly overexpressed 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.