Exploiting oxidative stress has recently emerged as a plausible strategy for 
treatment of human cancer, and antioxidant defenses are implicated in resistance 
to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses 
could thus broadly improve therapeutic outcomes. Here, we identify the 
AMPK-related kinase NUAK1 as a key component of the antioxidant stress response 
pathway and reveal a specific requirement for this role of NUAK1 in colorectal 
cancer. We show that NUAK1 is activated by oxidative stress and that this 
activation is required to facilitate nuclear import of the antioxidant master 
regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT 
activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear 
import. Deletion of NUAK1 suppresses formation of colorectal tumors, whereas 
acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. 
Importantly, elevated expression of NUAK1 in human colorectal cancer is 
associated with more aggressive disease and reduced overall 
survival.Significance: This work identifies NUAK1 as a key facilitator of the 
adaptive antioxidant response that is associated with aggressive disease and 
worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 
inhibition may provide a safe and effective means for treatment of human 
colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer 
Discov; 8(5); 632-47. ©2018 AACR.This article is highlighted in the In This 
Issue feature, p. 517.