2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.02F.05 Lysosomal Calciumrelease via TRPML3 Enhances Drug Sensitivity of Gefitinib-resistance NSCLS Cells

EP.02F.05 Lysosomal Calciumrelease via TRPML3 Enhances Drug Sensitivity of Gefitinib-resistance NSCLS Cells

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The study investigates the role of lysosomal calcium release via the TRPML3 channel in enhancing drug sensitivity to gefitinib in non-small cell lung cancer (NSCLC) cells, particularly those resistant to the drug. NSCLC resistance to gefitinib is linked with increased lysosomal exocytosis and exosomal release observed in the resistant HCC827/GR cells compared to sensitive HCC827 cells. The researchers identified an upregulation of TRPML3 expression in resistant cells. TRPML3, an endo-lysosomal calcium channel, facilitates lysosomal calcium release triggered by changes in lysosomal pH due to prolonged gefitinib exposure, which in turn increases lysosomal trafficking and exosomal secretion.<br /><br />The study used methods like ratiometric assays, flow cytometry, western blot analysis, and enzymatic activity assessments to evaluate calcium signaling, lysosomal pH, and exocytosis processes. Intriguingly, when TRPML3 was depleted in gefitinib-resistant cells, there was increased sensitivity to gefitinib, as evidenced by inhibited cell proliferation and increased cell death. This indicates that TRPML3 plays a vital role in drug resistance by regulating lysosomal behaviors and exosomal dynamics.<br /><br />Thus, TRPML3 emerges as a novel molecular factor in the development of drug resistance in cancer therapy. The study's findings contribute to a better understanding of cellular mechanisms underlying acquired drug resistance to targeted therapies like tyrosine kinase inhibitors in NSCLC, suggesting potential targets for improving therapeutic efficacy against drug-resistant cancer cells.

Asset Subtitle

Sei-hoon Yang

Meta Tag

Speaker Sei-hoon Yang

Topic Tumor Biology – Preclinical Biology

Keywords

TRPML3

lysosomal calcium release

gefitinib sensitivity

NSCLC

drug resistance

lysosomal exocytosis

exosomal release

HCC827/GR cells

calcium signaling

tyrosine kinase inhibitors