The Anti-tumor Potential Of Combining Fibroblast Growth Factor Receptor Inhibitors And Immune Checkpoint Inhibitors

Objective:To analyze the anti-tumor potential of combining fibroblast growth factor receptor inhibitors and immune checkpoint inhibitors(ICIs).Anti-angiogenesis drugs include single-target tyrosine kinase inhibitors(TKIs)and multi-target TKIs.Among them,VEGFR and FGFR serve as the targets of single-target TKIs and one of the targets of multi-target TKIs.At present,anti-angiogenesis therapy combined with ICIs therapy has played an anti-tumor synergistic role in a variety of solid tumors,among them,there are many studies on VEGFR inhibitors combined with ICIs and clear conclusions have been reached.However,FGF/FGFR as a compensatory pathway of VEGF/VEGFR pathway is not clearly studied.Therefore,it is necessary to analyze the anti-tumor potential of combining FGFR inhibitors and ICIs.Methods:1.Using the STRING protein databases to obtain the correlation data between anti-angiogenesis drugs and ICIs related target genes.2.Using the UCSC Xena and GEPIA databases,the correlation coefficients between anti-angiogenesis drugs and ICIs related target genes were obtained,and visualized with R-language.3.Using the UALCAN databases,the gene expression of anti-angiogenesis drugs and ICIs related targets were obtained,and visualized with R-language.4.Using the cBioPortal for Cancer Genomics databases,the gene mutation information of anti-angiogenesis drugs and ICIs related targets were obtained,and visualized with R-language.5.The antiangiogenesis drugs and ICIs related target genes of KEGG(Kyoto Encyclopedia of Genes and Genomes)and GO(Gene Ontology)pathway enrichment maps were visualized with R-language.Results:1.In a variety of tumors,there are a wide correlation between VEGFR and FGFR protein,and between VEGFR and PDL1/CTLA4 protein.2.In a variety of tumors,there is a wide and high correlation between FLT1/KDR/FLT4 and FGFR1-4 gene;there is a high correlation between FLT1/KDR and CD274 gene.3.In liver cancer,there was a strong positive correlation between FLT1/KDR/FLT4 and FGFR1-3 genes,and also a positive correlation between FGFR1-4 and PDCD1/CD274 genes;in thyroid cancer,there was a positive correlation between FLT1/KDR/FLT4 and FGFR1-4 genes,while there was a negative correlation between FGFR2-4 and PDCD1/CD274/CTLA4 genes.4.The antiangiogenesis drugs and ICIs related target genes are highly expressed in cholangiocarcinoma,skin cutaneous melanoma,breast cancer,and liver cancer.5.Each gene generated gene mutation in different types of cancer,and multiple genes generated gene mutation in each cancer.6.FGFR1-4 and FLT1/KDR/FLT4 are enriched in RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways.Conclusion:1.In cancers with a positive correlation between FGFR and immune checkpoints,using FGFR inhibitors in combination with ICIs may has the potential for anti-tumor synergistic effect.2.In cancers with a high expression of FGFR and immune checkpoint,using FGFR inhibitors in combination with ICIs may has the potential for anti-tumor synergistic effect.3.In cancers with a high frequency gene mutations of FGFR and immune checkpoint,using FGFR inhibitors in combination with ICIs may has the potential for anti-tumor synergistic effect.4.FGF/FGFR activated signaling up-regulated the expression level of PDL1 by activating MAPK and PI3K-AKT two downstream signaling pathways,thus inducing tumor cells to escape immune surveillance.Therefore,using FGFR inhibitors combined with ICIs may has the potential of anti-tumor synergistic effect.