Our findings that high levels of PIDD prevent NRF2 ubiquitination and promote its stabilization, and are associated with increased NRF2 and target gene expression in NSCLC patient samples, suggest that PIDD-mediated NRF2 activation may have also been a major factor driving chemoresistance in the mouse lung tumors. Here, NFE2L2 is linked to non-small cell lung carcinoma.