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(Slides)

Back to course

Pdf Summary

Researchers from Hangzhou Cancer Institution at Zhejiang University School of Medicine have discovered that cancer-associated fibroblasts (CAFs) can confer resistance to the third-generation EGFR-TKI drug osimertinib in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. To overcome this resistance, the researchers conducted a high-throughput screening and identified ceritinib as a potential drug candidate capable of reversing CAFs-induced osimertinib resistance. Ceritinib is an inhibitor for ALK/IGFR1/FAK kinases, and it showed a significant sensitizing effect on osimertinib resistance in NSCLC cells. In vivo experiments using xenograft tumor models in mice confirmed that ceritinib enhanced the sensitivity of tumors implanted with a combination of NSCLC cells and CAFs to osimertinib.<br /><br />Further analysis revealed that apoptotic NSCLC cells could induce the transformation of CAFs into normal fibroblasts (NFs) by decreasing the expression of α-SMA, a marker for CAFs activation. Co-culture experiments showed that the expression levels of IGF1, IGF2, and IGFIR in both CAFs and NSCLC cells were highly upregulated, indicating the activation of autocrine/paracrine IGF response. Ceritinib was able to target the IGF signaling pathway and reverse the CAFs-induced osimertinib resistance.<br /><br />Overall, this study provides valuable insights into the role of CAFs in osimertinib resistance and identifies ceritinib as a potential therapeutic option for overcoming this resistance in NSCLC patients with EGFR mutations. Further research is needed to validate these findings in clinical settings and explore the efficacy of ceritinib in combination therapy with osimertinib.

Asset Subtitle

hongfang zhang

Meta Tag

Speaker hongfang zhang

Topic Tumor Biology: Translational Biology - Drug Resistance

Keywords

cancer-associated fibroblasts

osimertinib resistance

non-small cell lung cancer

EGFR mutations

ceritinib

ALK/IGFR1/FAK kinases

NSCLC cells

α-SMA marker

autocrine/paracrine IGF response

combination therapy