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Anlotinib,a multitarget tyrosine kinase inhibitor,is effective as a third-line treatment against non-small cell lung cancer (NSCLC).However,acquired resistance occurs during its administration.To understand the molecular mechanisms of anlotinib resistance,we characterized chromatin accessibility in both the parental and anlotinib-resistant lung cancer cell line NCI-H1975 through ATAC-seq.Compared with the parental cells,we identified 2666 genomic regions with greater accessibility in anlotinib-resistant cells,in which angiogenesis-related processes and the motifs of 21 transcription factors were enriched.Among these transcription factors,TFAP2A was upregulated.TFAP2A knockdown robustly diminished tumor-induced angiogenesis and partially rescued the anti-angiogenic activity of anlotinib.Furthermore,transcriptome analysis indicated that 2280 genes were downregulated in anlotinib-resistant cells with TFAP2A knocked down,among which the PDGFR,TGF-β,and VEGFR signaling pathways were enriched.Meanwhile,we demonstrated that TFAP2A binds to accessible sites within BMP4 and HSPG2.Collectively,this study suggests that TFAP2A accelerates anlotinib resistance by promoting tumor-induced angiogenesis.