Issues

Activation of the KEAP1–NFE2L2 stress-response pathway has been implicated as a potential cause of resistance to radiotherapy in non–small cell lung cancer (NSCLC). In a study of 232 patients with NSCLC undergoing radiotherapy or surgery with curative intent, Binkley, Jeon, and colleagues found that loss-of-function mutations in KEAP1 or gain-of-function mutations in NFE2L2 were associated with increased risk of local recurrence after treatment. In vitro, treatment with a glutaminase inhibitor increased the susceptibility of radiation-resistant KEAP1- and NFE2L2-mutant lung cancer cells to radiation, consistent with recent work showing that glutamine metabolism is a dependency in KEAP1-deficient cells. For more information, see the article by Binkley, Jeon, and colleagues on page 1826.