2024 World Conference on Lung Cancer (WCLC) - Posters-P3.03I.11 The ATXN3-USP25-TRMT1 Axis Regulates tRNAm2,2G Modification and Promotes Osimertinib Resistance in Lung Cancer

P3.03I.11 The ATXN3-USP25-TRMT1 Axis Regulates tRNAm2,2G Modification and Promotes Osimertinib Resistance in Lung Cancer

Back to course

Pdf Summary

The study titled "The ATXN3-USP25-TRMT1 Axis Regulates tRNAm2,2G Modification and Promotes Osimertinib Resistance in Lung Cancer" investigates the mechanisms behind acquired osimertinib resistance in patients with advanced non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is initially effective but faces challenges due to emerging resistance.<br /><br />Research identifies the critical role of deubiquitinase enzymes (DUBs) in cancer progression and their potential link to drug resistance. The study highlights the overexpression of the ATXN3 protein in osimertinib-resistant lung adenocarcinoma cells, correlating it with poor patient prognoses. ATXN3 is found to stabilize USP25 through a deubiquitination process, which in turn regulates the TRMT1 enzyme.<br /><br />TRMT1 impacts tRNA modifications, specifically m2,2G, affecting the efficiency of translating key redox enzymes like GPX4 and SOD2. This regulation helps reduce reactive oxygen species (ROS) within cells, contributing to osimertinib resistance. Resistant cells showed higher modification levels, enhancing drug resistance by lowering ROS and bolstering cell proliferation.<br /><br />The study's methodology involved mass spectrometry, co-immunoprecipitation, and Western Blot analyses to unravel the interaction within the ATXN3-USP25-TRMT1 axis. Treatment models using osimertinib-resistant cells and organoids with the USP25 inhibitor AZ1 showed promising results. AZ1, alone or in combination with osimertinib, significantly inhibited cell and organoid proliferation. Animal model experiments further confirmed that USP25 or TRMT1 knockdown inhibited tumor growth.<br /><br />Ultimately, these findings suggest targeting the ATXN3-USP25-TRMT1 axis could be an effective strategy to combat osimertinib resistance, offering hope for enhancing therapeutic efficacy in resistant NSCLC patients.

Asset Subtitle

Tianqing Chu

Meta Tag

Speaker Tianqing Chu

Topic Tumor Biology – Translational Biology

Keywords

osimertinib resistance

lung cancer

ATXN3 protein

USP25

TRMT1 enzyme

tRNA modification

reactive oxygen species

EGFR-TKI

drug resistance

NSCLC