The combination of pralsetinib and bevacizumab enhances antitumor activity against KIF5B-RET lung cancer via PI3K/AKT pathway.

BACKGROUND: Although pralsetinib has shown promising efficacy in rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), acquired resistance remains a major clinical challenge and requires effective combination strategies. The study aims to explore the antitumor efficacy of the combined treatment of pralsetinib and bevacizumab in RET fusion-positive NSCLC. METHODS: Ba/F3 stably expressing KIF5B-RET and subsequent pralsetinib resistant cell line were used for evaluating the antitumor efficacy in vitro and in vivo. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the proliferative ability of Ba/F3 cell lines. The vascular endothelial growth factor (VEGF) levels in the cell supernatant were detected using the enzyme-linked immunosorbent assay (ELISA) method. Blood vessels in tumor were detected by Immunohistochemical staining. RESULTS: In this study, we demonstrated that the anti-angiogenic agent bevacizumab combined with pralsetinib can increase the sensitivity of Ba/F3 cells harboring KIF5B-RET fusion to pralsetinib through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Through ELISA, we observed that the levels of VEGF were elevated when the cell line developed drug resistance. Furthermore, in vivo experiment showed that combination therapy reduced microvessel density, decreased tumor volume, and significantly inhibited the PI3K/AKT pathway. CONCLUSIONS: Collectively, our results suggest that the combination of pralsetinib and bevacizumab is a promising approach for treating RET fusion-positive NSCLC.