AIM: To investigate the molecular mechanisms of KG-1 cell proliferation by profiling its responses to various protein kinase inhibitors. METHODS: CCK-8 assay, real time quantitative PCR (qRT-PCR) and Western-blot were used to detect the effect of various protein kinase inhibitors on KG-1 cell proliferation, the expression levels of mRNA and phosphorylation level of signaling proteins in the FGFR1 downstream pathways. RESULTS: NVP-BGJ398 and PD173074 effectively inhibited the proliferation of KG-1 cells, indicative of a crucial role of FGFR downstream signaling. After treatment with FGFR inhibitors, the levels of p-FGFR1OP2-FGFR1 and p-STAT5 decreased significantly (P<0.001), p-AKT decreased slightly (P<0.05), without affecting the p-ERK level (P>0.05). CONCLUSION: FGFR1OP2-FGFR1 mainly acts on the downstream STAT5 signaling pathway to promote cell proliferation. Comprehensive protein kinase inhibition analysis is a reliable and direct approach to identify functional drivers of cancer cell proliferation.