Concise Review: Gene of The Month KEAP1-mutant non-small cell lung cancer: the catastrophic failure of a cell-protecting hub

Abstract

Mutations in the KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (Nuclear factor erythroid 2-related factor 2) pathway are common in non-small cell lung cancer (NSCLC), albeit with a prevalence of KEAP1 mutations in lung adenocarcinoma (LUAD) and an equal representation of KEAP1 and NFE2L2 (the gene encoding for NRF2) alterations in lung squamous cell carcinoma (LUSC). The KEAP1-NRF2 axis is a crucial modulator of cellular homeostasis, enabling cells to tolerate oxidative and metabolic stresses, as well as xenobiotics. The complex cytoprotective response orchestrated by NRF2-mediated gene transcription embraces detoxification mechanisms, ferroptosis protection and metabolic reprogramming. Given that the KEAP1-NRF2 pathway controls core cellular functions, it is not surprising that a number of clinical studies connected KEAP1 mutations to increased resistance to chemotherapy, radiotherapy and targeted agents. More recently, an immune-cold tumor microenvironment was described as a typical feature of KEAP1-mutant LUAD. Consistently, a reduced efficacy of immunotherapy was reported in the KEAP1-mutant background. However, the connection between KEAP1 and immune-resistance seems more complex and dependent on coexisting genomic alterations. Given the clinical implications of deregulated KEAP1-NRF2 pathway in lung cancer, the development of pathway-directed anticancer treatments should be considered a priority in the domain of thoracic oncology.