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(Abstract)

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This study explores a potential therapeutic approach for treating non-small cell lung cancer (NSCLC) with hyperactivated NRF2, a protein associated with aggressive phenotypes and resistance to therapy. The researchers focus on targeting ferroptosis, a form of non-apoptotic cell death, as a strategy to overcome drug resistance in cancer treatment.<br /><br />The study shows that selectively targeting HDAC1/2, members of the histone deacetylase family, enhances ferroptotic cell death in NRF2-activated NSCLC. They find that hyperactivation of NRF2 in NSCLC cells reprograms SEs (super-enhancers) landscape associated with cMYC, which can be disrupted by HDAC1/2 inhibitors or other SEs inhibitors like compounds targeting BRD4, THZ1, or SWI/SNF. Disrupting SEs induces metabolic vulnerabilities in NRF2-activated cancer cells, making them more susceptible to ferroptosis.<br /><br />To improve clinical translational relevance, the researchers screen FDA-approved compounds and identify Dihydroartemisinin (DHA), a malaria treatment derivative, as a potent drug that induces ferroptosis and synergizes with the HDAC1/2 inhibitor Romidepsin.<br /><br />Overall, this study demonstrates that selectively targeting SEs enhances ferroptotic cell death in NRF2-activated NSCLC. The combination treatment of Romidepsin and DHA suggests a precision treatment strategy for this challenging-to-treat disease. This research provides valuable insights into the potential use of ferroptosis-induction therapy combined with super-enhancer inhibitors as a targeted approach for treating NRF2-activated lung cancer.

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

ferroptosis

HDAC1/2

SEs landscape

metabolic vulnerabilities

Dihydroartemisinin

Romidepsin

precision treatment strategy