2023 World Conference on Lung Cancer (Posters)-EP03.06. Synthetic Lethality Targeting Programmed Cell Death Reverses the Osimertinib Resistance Induced by ARID1A Deficiency in LUAD

EP03.06. Synthetic Lethality Targeting Programmed Cell Death Reverses the Osimertinib Resistance Induced by ARID1A Deficiency in LUAD - PDF(Abstract)

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This presentation discusses the findings of a study on the role of ARID1A deficiency in lung adenocarcinoma (LUAD) and its association with cancer progression and drug resistance. The researchers aimed to explore the downstream mechanisms of EZH2 inhibitors in ARID1A deficient cancers and its potential therapeutic implications.<br /><br />The study used ARID1A-knockdown LUAD cell lines to investigate the effects of ARID1A deficiency. RNA sequencing and mass spectrometry were performed to analyze gene and protein expression. Western blotting and immunohistochemistry were used to evaluate protein levels. The researchers also examined the effects of GSK-126, simvastatin, and osimertinib on ARID1A-knockdown cells.<br /><br />The results indicated a correlation between ARID1A and programmed cell death, as well as the Akt/mTOR pathway and autophagy. ARID1A deficiency upregulated the transcription of E2F1 and downregulated PTEN transcription, resulting in enhanced proliferation and tumorigenic ability. Additionally, ARID1A deficiency inhibited autophagy via the activation of the Akt/mTOR pathway. Notably, ARID1A deficiency increased proteasome function and decreased the degradation of P53 protein, which mediates programmed cell death.<br /><br />The study demonstrated that an EZH2 inhibitor, GSK-126, could reverse the cancer progression and osimertinib resistance induced by ARID1A deficiency. GSK-126 inhibited the Akt/mTOR pathway, improved autophagy levels, and showed sensitivity in ARID1A-knockdown cells.<br /><br />Overall, this research provides valuable insights into the mechanisms underlying ARID1A deficiency in LUAD and its potential as a therapeutic target. The findings highlight the potential of EZH2 inhibitors, such as GSK-126, in reversing the effects of ARID1A deficiency and overcoming drug resistance in LUAD.

Asset Subtitle

Dantong Sun

Meta Tag

Speaker Dantong Sun

Topic Tumor Biology: Translational Biology - Translational Therapeutics

Keywords

ARID1A deficiency

lung adenocarcinoma

cancer progression

drug resistance

EZH2 inhibitors

RNA sequencing

autophagy

proliferation

therapeutic target

GSK-126