2023 World Conference on Lung Cancer (Posters)-P1.12. Ferroptosis-induction Therapy Combined with Super-enhancers Inhibitors Selectively Target NRF2-activated Lung Cancer

P1.12. Ferroptosis-induction Therapy Combined with Super-enhancers Inhibitors Selectively Target NRF2-activated Lung Cancer - PDF(Slides)

Back to course

Pdf Summary

Researchers have identified a potential therapeutic strategy for treating non-small cell lung cancer (NSCLC) with hyperactivated NRF2, a genetic alteration frequently observed in the KEAP1-NFE2L2 pathway. Directly targeting NSCLC with hyperactivated NRF2 has been challenging, but the researchers found that inducing ferroptosis, a regulated form of non-apoptotic cell death, may be promising for overcoming drug resistance in cancer treatment.<br /><br />The study screened an epigenetic drug library and found that HDAC inhibitors sensitized cells to ferroptosis induction. They also identified that HDAC1/2 play a critical role in sensitizing cells to ferroptosis. The researchers discovered that disrupting super-enhancers, specific regions of the genome involved in gene regulation, enhanced the effectiveness of ferroptosis induction. Additionally, selectively targeting HDAC1/2 induced alterations in lipid metabolites, further promoting cell death.<br /><br />The synergistic effect of combining HDAC inhibitors with ferroptosis inducers was specifically observed in NRF2-activated NSCLC. The study also identified DHA as a potential substitute for RSL3, a commonly used ferroptosis inducer, suggesting a translatable treatment strategy for this challenging-to-treat disease.<br /><br />The researchers concluded that selectively targeting super-enhancers can enhance ferroptotic cell death, particularly in NRF2-activated NSCLC. The combination treatment of Romidepsin, an HDAC inhibitor, and DHA shows promise as a potential treatment strategy for this difficult-to-treat cancer.<br /><br />The study was supported by funding from the National Natural Science Foundation of China, the excellent talent program of Shanghai Chest Hospital, the Basic Foundation Program for Youth of Shanghai Chest Hospital, and the Innovative Research Team of High-level Local Universities in Shanghai.

Asset Subtitle

Ke Xu

Meta Tag

Speaker Ke Xu

Topic Tumor Biology: Translational Biology - Translational Therapeutics

Keywords

non-small cell lung cancer

NSCLC

hyperactivated NRF2

KEAP1-NFE2L2 pathway

therapeutic strategy

ferroptosis induction

HDAC inhibitors

super-enhancers

lipid metabolites

combination treatment