famitinib and Lung-Neoplasms

Combining antiangiogenic therapy with radioimmunotherapy is believed to further improve antitumor efficacy, but there is still a lack of evidence to support this. This study aimed to investigate the role of the tumor vascular-targeted agent famitinib with a combination of radiotherapy and an immune checkpoint inhibitor in murine lung cancer.. The effect of VEGFA and HIF1A on clinical prognosis and the tumor immune microenvironment was analyzed using public databases. Enrichment analyses of post-irradiation gene expression and mRNAs related to immunotherapy efficacy were carried out based on GEO datasets. A C57BL/6 mouse subcutaneous tumor model was used to evaluate the antitumor effects of different treatment schemes. The tumor immunophenotyping was identified by flow cytometry.. We demonstrated that high level of VEGFA and HIF1A expression in lung cancer was related to poor prognosis and immunosuppressive tumor microenvironment. In a mouse model, the triple therapy of famitinib, radiotherapy and immunotherapy had the most dramatic antitumor activity. It significantly increased tumor infiltrating lymphocytes and reversed the immunosuppressive state of the tumor microenvironment in mice. Compared with radioimmunotherapy, the addition of famitinib further promoted the infiltration of CD8+ T cells and M1 type tumor associated macrophages, and reduced the number of myeloid suppressor cells. Therefore, triple therapy converted the immunosuppressive tumor microenvironment into an immunostimulatory one.. Famitinib can synergize with radioimmunotherapy by regulating the tumor immune microenvironment in murine lung cancer.

Topics: Animals; Cell Line, Tumor; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Radioimmunotherapy; Tumor Microenvironment

As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy.. The combined antitumor effects of HS-10296, a third-generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non-small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies.. Famitinib strengthened the effects of HS-10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS-10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS-10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS-10296 and famitinib exerted synergistic antitumor activity in NCI-H1975 and PC-9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues.. Collectively, our results indicate that HS-10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third-generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR-mutant NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Protein Kinase Inhibitors; Pyrroles; Receptor Protein-Tyrosine Kinases; Signal Transduction