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KEAP1-Mutant NSCLC: The Catastrophic Failure of a Cell-Protecting Hub
Stefano Scalera1, Marco Mazzotta2, Clelia Cortile1
1SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Regina Elena National Cancer Institute, Rome, Italy.
Abstract:
Mutations in the KEAP1-NRF2 pathway are common in NSCLC, albeit with a prevalence of KEAP1 mutations in lung adenocarcinoma and an equal representation of KEAP1 and NFE2L2 (the gene encoding for NRF2) alterations in lung squamous cell carcinoma. The KEAP1-NRF2 axis is a crucial modulator of cellular homeostasis, enabling cells to tolerate oxidative and metabolic stresses, and 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 lung adenocarcinoma. Consistently, a reduced efficacy of immunotherapy was reported in the KEAP1-mutant background. Nevertheless, 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.
Insights
Mutations in the KEAP1-NRF2 pathway are frequent in non-small cell lung cancer (NSCLC), impacting cellular defense and treatment resistance. Targeting this pathway is crucial for developing new lung cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The KEAP1-NRF2 pathway regulates cellular homeostasis, protecting against oxidative and metabolic stress.
- Mutations in KEAP1 and NFE2L2 (NRF2) are prevalent in non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma and lung squamous cell carcinoma.
- This pathway controls detoxification, ferroptosis protection, and metabolic reprogramming.
Purpose of the Study:
- To investigate the role of KEAP1-NRF2 pathway alterations in NSCLC.
- To understand the implications of these mutations on treatment resistance and tumor microenvironment.
- To highlight the potential of targeting this pathway for novel anticancer strategies.
Main Methods:
- Analysis of mutation prevalence in different NSCLC subtypes.
- Review of clinical studies linking KEAP1 mutations to treatment resistance.
- Examination of the relationship between KEAP1 mutations and the tumor immune microenvironment.
Main Results:
- KEAP1 mutations are common in NSCLC, with specific patterns in lung adenocarcinoma and lung squamous cell carcinoma.
- KEAP1 mutations are associated with resistance to chemotherapy, radiotherapy, and targeted therapies.
- KEAP1-mutant lung adenocarcinoma often exhibits an immune-cold tumor microenvironment, leading to reduced immunotherapy efficacy.
Conclusions:
- The KEAP1-NRF2 pathway is a critical factor in NSCLC pathogenesis and treatment response.
- Deregulation of this pathway contributes to therapeutic resistance and immune evasion.
- Developing treatments targeting the KEAP1-NRF2 pathway is a priority for thoracic oncology.
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