Molecular Pathways Molecular Pathways: Targeting MYC-induced Metabolic Reprogramming and Oncogenic Stress in Cancer

MYC is amultifunctional transcription factor that is deregulated inmany human cancers. MYC impacts a collaborative genetic program that orchestrates cell proliferation, metabolism, and stress responses. Although the progression of MYC-amplified tumors shows robust dependence on MYC activity, directly targeting MYC as a therapeutic method has proven to be technically difficult. Therefore, alternative approaches are currently under development with a focus on interference withMYC-mediated downstream effects. To fuel rapid cell growth, MYC reprograms cancer cell metabolism in a way that is substantially different fromnormal cells. TheMYC-inducedmetabolic signature is characterized by enhanced glucose and glutamine uptake, increased lactate production, and altered amino acid metabolism. Targeting MYCreprogrammed cancer cell metabolism is considered to be promising based onmultiple preclinical studies. In addition, the increased biosynthetic demand ofMYC-driven tumors coupled with limited nutrient access within tumor microenvironments create multiple levels of oncogenic stress, which can also be used as tumor-specific targets for pharmacologic intervention. Presumably, the best therapeutic strategy for treating MYC-amplified tumors is combined targeting of multiple MYC-mediated pathways, especially those involved in regulating cell proliferation, metabolism, and oncogenic stress. Clin Cancer Res; 19(21);