目前有效根除或抑制三阴性乳腺癌（TNBC）肿瘤干细胞（CSCs）的策略还很有限，故研究新型具有抗CSCs功能的药物对于TNBC尤其是难治性TNBC的治疗有着重要的价值。课题组前期研究发现新型小分子酪氨酸激酶抑制剂DCC-2036可抑制TNBC细胞的成球能力，降低干细胞标志物的表达，并初步揭示酪氨酸激酶AXL和转录因子KLF5可能是DCC-2036抑制TNBC干细胞的关键靶点，且沉默AXL可能通过降低KLF5的蛋白稳定性降低其表达，而沉默KLF5可反过来在转录水平降低AXL的表达。因此，我们提出“DCC-2036可通过靶向AXL-KLF5正反馈调节机制在TNBC中发挥抑制肿瘤干细胞的作用”的科学假说。本课题拟从细胞、分子、整体水平揭示DCC-2036对TNBC干细胞的抑制作用，阐明介导其发挥作用的AXL-KLF5正反馈调节依赖机制。课题的完成可为难治性TNBC的治疗提供潜在的候选药物和靶点。

At present, the strategies for effectively eradicating or inhibiting triple-negative breast cancer (TNBC) cancer stem cells (CSCs) are still limited, so the study of new drugs with anti-CSCs function is of great value for the treatment of TNBC, especially the refractory TNBC. Our previous research has found that the novel small molecule tyrosine kinase inhibitor DCC-2036 inhibited the mammosphere formation in TNBC cells as well as reduced the expression of stem cell markers, and initially revealed that the tyrosine kinase AXL and the transcription factor KLF5 may be the key targets for DCC-2036 to inhibit TNBC stem cells. Moreover, silencing AXL may downregulate the expression of KLF5 by decreasing the protein stability of KLF5, whereas silencing KLF5 may in turn reduce the expression of AXL at the transcriptional level. Therefore, we propose a scientific hypothesis that "DCC-2036 may suppress the cancer stem cells in TNBC by targeting AXL-KLF5 positive feedback regulation mechanism". This study aims to reveal the inhibitory effect of DCC-2036 on TNBC stem cells from the cellular, molecular and integral level, and to elucidate the positive feedback regulation-dependent mechanism of AXL-KLF5 which mediates the function of DCC-2036. The completion of this project may provide potential candidates and targets for the treatment of refractory TNBC.