KEAP1/NRF2 (NFE2L2) mutations in NSCLC – Fuel for a superresistant phenotype?

The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients.