English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background and purpose  Targeted therapy and immunotherapy have led to dramatic change in the treatment of lung cancer, however, the overall 5-year survival rate of lung cancer patients is still suboptimal. It is important to exploit new potential of molecularly targeted therapies. High-frequency somatic mutations in  KEAP1/NRF2  (27.9%) have been identified in lung squamous cell carcinoma. In this research, we explored the role of  KEAP1  somatic mutations in the development of LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be potential to target lung cancer carrying  KEAP1/NRF2  mutations.    Methods  Lung cancer cell lines A549 and H460 with loss-of-function mutations in  KEAP1  stably transfected with wild-type (WT)  KEAP1  or somatic mutations in  KEAP1  were used to investigate the functions of somatic mutations in  KEAP1 . Flow cytometry, plate clone formation experiments, and scratch tests were used to examine reactive oxygen species, proliferation, and migration of these cell lines.    Results  The expression of NRF2 and its target genes increased ,  and tumor cell proliferation, migration, and tumor growth were accelerated in A549 and H460 cells stably transfected with  KEAP1  mutants compared to control cells with a loss-of-function  KEAP1  mutation and stably transfected with WT  KEAP1  in both in vitro and in vivo studies. The proliferation of A549 cell line trasfected with the R320Q  KEAP1  mutant was inhibited more apparent than that of the A549 cell line trasfected with WT  KEAP1  after treatment with NRF2 inhibitor ML385.    Conclusion  Somatic mutations of  KEAP1  identified from patients with LSCC likely promote tumorigenesis mediated by activation of the KEAP1/NRF2 antioxidant stress response pathway. NRF2 inhibition with ML385 could inhibit the proliferation of tumor cells with  KEAP1  mutation.Video abstract

Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation