Zebrafish Xenograft Model of Human Lung Cancer for Evaluating Osimertinib Resistance

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) patients with EGFR mutations often develop acquired resistance to first-generation tyrosine kinase inhibitors (TKIs) like Gefitinib, frequently through the T790M mutation.
• The third-generation EGFR-TKI Osimertinib is a targeted therapy for patients with EGFR and T790M mutations, but drug screening post-resistance remains challenging.

Purpose of the Study:

• To establish Gefitinib- and Osimertinib-resistant NSCLC cell lines for in vitro drug screening.
• To evaluate the in vitro and in vivo efficacy of Osimertinib against EGFR-mutated and T790M-resistant NSCLC.
• To utilize a zebrafish xenotransplantation model to assess Osimertinib's effects on tumor proliferation and angiogenesis.

Main Methods:

• Development of Gefitinib- and Osimertinib-resistant NSCLC cell lines.
• In vitro assessment of cell proliferation and drug sensitivity across various Osimertinib concentrations.
• Zebrafish xenotransplantation model to evaluate Osimertinib's impact on tumor growth and angiogenesis in vivo.

Main Results:

• Osimertinib demonstrated an inhibitory effect on the proliferation of resistant NSCLC cell lines in vitro.
• In vivo studies using zebrafish xenografts confirmed that Osimertinib inhibits tumor cell proliferation and angiogenesis.
• The observed effects of Osimertinib in the zebrafish model align with clinical findings.

Conclusions:

• Osimertinib is effective in inhibiting tumor cell proliferation in NSCLC models harboring EGFR mutations and the T790M resistance mutation.
• The zebrafish xenotransplantation model serves as a viable platform for evaluating targeted therapies like Osimertinib in NSCLC.
• These findings support the clinical utility of Osimertinib in managing acquired resistance to earlier-generation TKIs in NSCLC.