Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de Mexico 04510, Mexico.
Escuela de Medicina, Universidad Panamericana, Ciudad de Mexico 03920, Mexico.
Int J Mol Sci. 2022 Aug 5;23(15):8702. doi: 10.3390/ijms23158702.
Triple-negative breast cancer (TNBC) is associated with a poor prognosis and the absence of targeted therapy. c-Kit, a receptor tyrosine kinase (RTK), is considered a molecular target for anticancer drugs. Tyrosine kinase inhibitors (TKIs) recognizing c-Kit are used for the treatment of c-Kit-expressing tumors. However, the expression, function, and therapeutic potential of c-Kit have been little explored in TNBC. Here, we studied the expression and effects of c-Kit in TNBC through in vitro and in silico analysis, and evaluated the response to TKIs targeting c-Kit. Analysis of TNBC cells showed the expression of functional c-Kit at the cell membrane. The stimulation of c-Kit with its ligand induced the activation of STAT3, Akt, and ERK1/2, increasing cell migration, but had no effect on cell proliferation or response to Doxorubicin. Analysis of public datasets showed that the expression of c-Kit in tumors was not associated with patient survival. Finally, TNBC cells were susceptible to TKIs, in particular the effect of Nilotinib was stronger than Doxorubicin in all cell lines. In conclusion, TNBC cells express functional c-Kit, which is a targetable molecule, and show a strong response to Nilotinib that may be considered a candidate drug for the treatment of TNBC.
三阴性乳腺癌（TNBC）与预后不良和缺乏靶向治疗有关。c-Kit 是一种受体酪氨酸激酶（RTK），被认为是抗癌药物的分子靶点。识别 c-Kit 的酪氨酸激酶抑制剂（TKI）用于治疗 c-Kit 表达的肿瘤。然而，c-Kit 在 TNBC 中的表达、功能和治疗潜力尚未得到充分探索。在这里，我们通过体外和计算分析研究了 c-Kit 在 TNBC 中的表达和作用，并评估了针对 c-Kit 的 TKI 的反应。对 TNBC 细胞的分析表明，功能性 c-Kit 在细胞膜上表达。c-Kit 与其配体的刺激诱导了 STAT3、Akt 和 ERK1/2 的激活，增加了细胞迁移，但对细胞增殖或阿霉素的反应没有影响。对公共数据集的分析表明，肿瘤中 c-Kit 的表达与患者的生存无关。最后，TNBC 细胞对 TKI 敏感，特别是尼罗替尼在所有细胞系中的作用强于阿霉素。总之，TNBC 细胞表达功能性 c-Kit，这是一个可靶向的分子，并对尼罗替尼表现出强烈的反应，尼罗替尼可能被认为是治疗 TNBC 的候选药物。
