PO.TB03.01 · 肿瘤生物学
双重TTK/PLK1抑制联合G-CSF治疗协同抑制三阴性乳腺癌的转移进展
Dual TTK/PLK1 inhibition combined with G-CSF treatment synergistically suppresses metastatic progression in triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
苏氨酸酪氨酸激酶（TTK）和polo样激酶1（PLK1）是纺锤体组装检查点（SAC）的关键调控因子，为忠实的有丝分裂进程所必需，在人类癌症中经常过表达和失调。近年来，靶向SAC（包括TTK和/或PLK1）的策略已成为癌症治疗中有前景的治疗途径。然而，这些SAC抑制剂已知会引起不良反应，包括中性粒细胞减少。粒细胞集落刺激因子（G-CSF）被广泛用于预防抗癌治疗诱导的中性粒细胞减少，但越来越多的证据表明G-CSF也可能促进肿瘤进展。在此，我们证明了一种新型双重TTK/PLK1抑制剂BAL0891的广泛抗癌活性，及其与转移性乳腺癌中G-CSF/G-CSF受体（G-CSFR）轴的功能联系。在乳腺癌患者中，与其他亚型相比，TTK和PLK1在表现出侵袭性行为的三阴性乳腺癌（TNBC）中均显著上调，且其表达水平在TNBC患者中呈正相关。与正常组织相比，G-CSFR的表达在乳腺肿瘤中上调，并在转移性肿瘤中进一步升高。在多种人源和鼠源TNBC细胞系中，BAL0891发挥了强效的抗增殖活性，伴随G2/M细胞周期阻滞和凋亡。BAL0891在TNBC细胞中的效力（GI50约50-90 nM）显著高于永生化的MCF10A和ER+ MCF7细胞（GI50 > 700 nM）。此外，BAL0891治疗抑制了转移性TNBC细胞的迁移和侵袭能力，同时伴有波形蛋白（vimentin，一种上皮-间充质转化（EMT）标志物）表达的降低。当比较BAL0891单独使用以及与G-CSF联合使用对TNBC进展的影响时，在具有中至高G-CSFR水平的TNBC细胞中，G-CSF治疗并未改变对BAL0891的抗增殖或凋亡应答。然而，BAL0891与G-CSF联合治疗进一步增强了BAL0891介导的对这些细胞迁移和侵袭的抑制。综上所述，这些发现提示双重TTK/PLK1抑制联合G-CSF可能代表一种有价值的治疗策略，可抑制转移性TNBC，同时潜在地降低中性粒细胞减少的风险。
查看英文原文 English abstract
Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1), critical regulators of the spindle assembly checkpoint (SAC) required for faithful mitotic progression, are frequently overexpressed and dysregulated in human cancers. In recent years, strategies targeting the SAC, including TTK and/or PLK1, have emerged as promising therapeutic approaches in cancer treatment. However, these SAC inhibitors are known to induce adverse effects, including neutropenia. Granulocyte-colony stimulating factor (G-CSF) is widely used to prevent anti-cancer therapy-induced neutropenia, but growing evidence suggests that G-CSF may also promote tumor progression. Here, we demonstrate the broad anti-cancer activity of a novel dual TTK/PLK1 inhibitor, BAL0891, and its functional link to the G-CSF/G-CSF receptor (G-CSFR) axis in metastatic breast cancer. In patients with breast cancer, both TTK and PLK1 were markedly upregulated in triple-negative breast cancer (TNBC), which exhibits aggressive behavior, compared with other subtypes, and their expression levels were positively correlated among TNBC patients. The expression of G-CSFR was upregulated in breast tumors compared with normal tissues and was further elevated in metastatic tumors. In multiple human and murine TNBC cell lines, BAL0891 exerted potent anti-proliferative activity, accompanied by G2/M cell-cycle arrest and apoptosis. BAL0891 showed markedly higher potency in TNBC cells (GI50 ≈ 50─90 nM) than in immortalized MCF10A and ER+ MCF7 cells GI50 > 700 nM). In addition, BAL0891 treatment suppressed the migratory and invasive capacities of metastatic TNBC cells, with a concomitant reduction in vimentin expression, an epithelial-mesenchymal transition (EMT) marker. When comparing the effects of BAL0891 alone and in combination with G-CSF on TNBC progression, G-CSF treatment did not alter the anti-proliferative or apoptotic responses to BAL0891 in TNBC cells harboring moderate to high G-CSFR levels. However, combined BAL0891 and G-CSF treatment further potentiated BAL0891-mediated suppression of migration and invasion in these cells. Taken together, these findings suggest that dual TTK/PLK1 inhibition in combination with G-CSF may represent a valuable therapeutic strategy to suppress metastatic TNBC while potentially reducing the risk of neutropenia.
利益披露 Disclosure
S. Kim, None..
H. Kim, None..
S. Cho, None..
J. Lee, None..
M. Park, None..
M. Kang, None..
S. Ma, None..
H. Choi, None..
J. Lee, None.