Anlotinib enhances the anti-tumor activity of osimertinib in patients with non-small cell lung cancer by reversing drug resistance.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly improves the prognosis of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, subsequently-acquired resistance limits its effectiveness. This study aimed to explore the efficacy of anlotinib, a multitarget inhibitor of angiogenesis, in combination with osimertinib using in vitro and in vivo EGFR-TKI-sensitive and EGFR-TKI-resistant models. METHODS: We established osimertinib-resistant cell lines (H1975-OR and PC9-OR) and evaluated the effects of osimertinib, anlotinib, and their combination on cell proliferation in vivo and in vitro. In addition, we used pleural fluid from nine patients with EGFR-mutant NSCLC who received osimertinib therapy in the clinic to successfully establish a zebrafish patient-derived xenograft (zPDX) model. The effect of the combined treatment in vivo was assessed by quantifying red fluorescent regions representing tumor cell growth in zebrafish embryos to assess tumor proliferation and migration. RESULTS: Combination osimertinib and anlotinib therapy did not have an obvious synergistic antiproliferative effect in parental H1975 and PC9 cells; however, anlotinib reversed osimertinib resistance in osimertinib-resistant H1975-OR and PC9-OR cells in vivo and in vitro. A similar phenomenon was observed in the zPDX model. CONCLUSIONS: In conclusion, anlotinib did not significantly enhance the anti-tumor effects of osimertinib in osimertinib-sensitive NSCLC cell lines or a zPDX model. However, it partially reversed osimertinib resistance. This combination therapy may improve the outcomes of patients with advanced NSCLC showing osimertinib-resistance.