布鲁顿酪氨酸激酶靶向药物的研究进展

布鲁顿酪氨酸激酶（Bruton's tyrosine kinase，BTK）是B细胞抗原受体信号转导通路中的关键激酶，参与B细胞增殖、分化和凋亡的调节，同时在多种信号通路的调控及肿瘤和炎症的发生和发展中也起着重要作用，已成为治疗恶性血液病和自身免疫性疾病的重要靶点。目前已上市的BTK靶向药物依鲁替尼、阿卡替尼和泽布替尼，对B细胞恶性肿瘤显示出较好的临床疗效，此外已有多个药物进入临床研究，表现出较好的开发前景。靶向BTK的靶向蛋白降解嵌合体分子的发展，有望解决依鲁替尼引起的耐药，更好地推动BTK靶向药物的研发。本文主要对BTK靶向药物的研究进展进行综述，为合理开发BTK靶向药物提供启示。

Progress on Bruton's Tyrosine Kinase Targeted Drugs

ABSTRACT: OBJECTIVE To investigate the mechanism of sinomenine (SIN) reversing drug resistance of human breast cancer MCF-7 cells to tamoxifen (TAM). METHODS MCF-7 cells were stimulated by TAM at high concentration for a short time to induce drug resistance, and the changes of drug resistance were detected by MTT assay; The toxic effects of SIN and TAM on drug-resistant strain MCF-7/TAM were further detected by MTT assay, and the combination index of the two drugs combined was analyzed by CompuSyn software to evaluate the combination effect; Flow cytometry was used to detect the effects of the two drugs on the apoptosis and cell cycle of MCF-7/TAM cells; Western blot assay was used to detect the expression of PI3K/AKT/mTOR signaling pathway related proteins in MCF-7/TAM cells, as well as the expression of PI3K/AKT/mTOR signaling pathway related proteins in MCF-7/TAM cells after SIN intervention. RESULTS The sensitivity of MCF-7/TAM cell line to TAM was significantly reduced, and the drug resistance model was successfully constructed; Both SIN and TAM can dose-dependently inhibit the proliferation of MCF-7/TAM cells, and the sensitivity of MCF-7/TAM cells to TAM was significantly increased after SIN intervention; CompuSyn software analysis showed that the two drugs were synergistic; Phosphorylation levels of PI3K, Akt and mTOR in MCF-7/TAM cells were significantly higher than those in MCF-7 cells. After SIN intervention, phosphorylation levels of PI3K, Akt and mTOR in MCF-7/TAM cells were significantly reduced. CONCLUSION Sinomenine can effectively reverse the resistance of MCF-7 cells to tamoxifen, possibly by inhibiting the PI3K/AKT/mTOR signaling pathway.