Abstract
The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within KEAP1/ NRF2 are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.
Highlights
The disruption of cellular redox state and nutrient metabolism is a crucial barrier to tumorigenesis that widely intersects with pathways regulating cell proliferation, stress response, genome stability, and bioenergetics
The KEAP1/NRF2 pathway exhibits significant pleiotropic effects extending beyond redox homeostasis, including effects in cellular differentiation, nutrient metabolism, and immune modulation; this ability to interact with a diverse array of pathways may explain why KEAP1/NRF2 mutations are selected for in many cancers
KEAP1 is positioned as a key coordinator of the metabolic, redox, and environmental stress response of a cell, given that activation of geno- and cytoprotective pathways requires significant energy and metabolic substrate investment; the constitutive strain on carbon and sulfur substrates leads to a depletion of tricarboxylic acid (TCA) cycle intermediates and a selection for the reorganization of cysteine metabolism (Figure 2)
Summary
The disruption of cellular redox state and nutrient metabolism is a crucial barrier to tumorigenesis that widely intersects with pathways regulating cell proliferation, stress response, genome stability, and bioenergetics. The KEAP1/NRF2 pathway exhibits significant pleiotropic effects extending beyond redox homeostasis, including effects in cellular differentiation, nutrient metabolism, and immune modulation; this ability to interact with a diverse array of pathways may explain why KEAP1/NRF2 mutations are selected for in many cancers.
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