2023 World Conference on Lung Cancer (Posters)-EP03.02. High-Throughput Screening Reveals Ceritinib as a Sensitizer for Cafs-Induced Osimertinib Resistance in Non-small Cell Lung Cancer

EP03.02. High-Throughput Screening Reveals Ceritinib as a Sensitizer for Cafs-Induced Osimertinib Resistance in Non-small Cell Lung Cancer - PDF(Abstract)

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This study focused on non-small cell lung cancer (NSCLC) and the development of resistance to the drug osimertinib. The researchers discovered that cancer-associated fibroblasts (CAFs), which are present in the fibrotic stroma of NSCLC tumors, can confer resistance to osimertinib. The aim of the study was to find potential drugs that could reverse this CAF-induced resistance.<br /><br />The researchers conducted high-throughput screening using a library of cytokine/chemokine inhibitors to test the combination effect of osimertinib and 209 inhibitors on the viability of NSCLC cells. They found that ceritinib, an inhibitor for ALK/IGFR1/FAK kinases, showed a significant sensitizing effect on CAFs-induced osimertinib resistance in NSCLC cells.<br /><br />In vivo experiments were performed using xenograft tumor models in mice. The combination of osimertinib and ceritinib was tested in tumors implanted with NSCLC cells alone or combined with CAFs. The results showed that ceritinib significantly enhanced osimertinib sensitivity in tumors implanted with the combination of NSCLC cells and CAFs, but did not affect sensitivity in tumors implanted with NSCLC cells only.<br /><br />Further analysis revealed that apoptotic NSCLC cells induced the transformation of CAFs into normal fibroblasts (NFs) by decreasing the expression of α-SMA, a marker of CAF activation. The expression levels of IGF1, IGF2, and IGFIR in both CAFs and NSCLC cells were upregulated, indicating the activation of autocrine/paracrine IGF response.<br /><br />In conclusion, ceritinib was found to reverse CAFs-induced osimertinib resistance in NSCLC cells by targeting the IGF signaling pathway. This study highlights the potential of targeting CAFs and the IGF pathway as a strategy for overcoming drug resistance in NSCLC patients with EGFR mutations.

Asset Subtitle

hongfang zhang

Meta Tag

Speaker hongfang zhang

Topic Tumor Biology: Translational Biology - Drug Resistance

Keywords

non-small cell lung cancer

NSCLC

drug resistance

osimertinib

cancer-associated fibroblasts

CAFs

ceritinib

ALK/IGFR1/FAK kinases

in vivo experiments

IGF signaling pathway