Mutations in the KEAP1-NFE2L2 Pathway Define a Molecular Subset of Rapidly Progressing Lung Adenocarcinoma

Abstract

Introduction: Molecular characterization studies revealed recurrent kelch like ECH associated protein 1 gene (KEAP1)/nuclear factor, erythroid 2 like 2 gene (NFE2L2) alterations in NSCLC. These genes encode two interacting proteins (a stress response pathway [SRP]) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations have an impact on clinical outcomes is unclear. Methods: We performed amplicon-based next-generation sequencing to characterize the SRP in patients with metastatic NSCLC (Regina Elena National Cancer Institute cohort [n ¼ 88]) treated with first-line chemotherapy. Mutations in the DNA damage response (tumor protein p53 gene [TP53], ATM serine/threonine kinase gene [ATM], and ATR serine/threonine kinase gene [ATR]) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of phosphorylated ataxia telangiectasia mutated kinase and ataxia telangiectasia and Rad3-related protein. Two independent cohorts (the Memorial Sloan Kettering Cancer Center cohort and The Cancer Genome Atlas cohort) with data from approximately 1400 patients with advanced LAC were used to assess the reproducibility of the results.Results: In the Regina Elena National Cancer Institute cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival and overall survival than their wild-type counterparts did (log-rank p ¼ 0.006 and p ¼ 0.018, respectively). This association was driven by LAC in which KEAP1/NFE2L2 mutations were overrepresented in

The NRF2, Thioredoxin, and Glutathione System in Tumorigenesis and Anticancer Therapies

“…KEAP1/NFE2L2 mutations in metastatic lung adenocarcinoma are linked with a chemotherapy-resistant subtype and more progressive disease. [80] NSCLC patients with brain metastasis have mutations in the KEAP1-NRF2-ARE pathway that provide a survival advantage and dissemination of circulating tumor cells.…”

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma

“…KRAS mutations are associated with poor response to anti-cancer drug treatments (3)(4)(5). Furthermore, additional genetic alterations often coexisting with oncogenic KRAS, such as inactivating mutations in STK11 or KEAP1, enhance the chemoresistant phenotype (6). Mechanistically, chemoresistance may be a consequence of: (a) drug inactivation, (b) reduced drug uptake, (c) increased drug efflux, or (d) enhanced repair of treatment-induced DNA lesions by DNA repair mechanisms (7).…”

Downregulation of the ubiquitin ligase KBTBD8 prevented epithelial ovarian cancer progression

“…For example, in lung adenocarcinoma (LAC) cohorts, patients who carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter survival. These patients had elevated expression of ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), which are two important kinases involved in tumorigenesis (Goeman et al 2019 ). ZBTB28/BCL6B/BAZF is a BTB/POZ domain protein methylated in multiple tumors.…”