Molecular Pathways: Targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer.

Abstract

MYC is a multifunctional transcription factor that is deregulated in many 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 with MYC-mediated downstream effects. To fuel rapid cell growth, MYC reprograms cancer cell metabolism in a way that is substantially different from normal cells. The MYC-induced metabolic signature is characterized by enhanced glucose and glutamine uptake, increased lactate production, and altered amino acid metabolism. Targeting MYC-reprogrammed cancer cell metabolism is considered to be promising based on multiple preclinical studies. In addition, the increased biosynthetic demand of MYC-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.