Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer
Degradation of MCL-1 by bufalin reverses acquired resistance to osimertinib in EGFR-mutant lung cancer
复制标题
蟾毒灵降解 MCL-1 可逆转 EGFR 突变型肺癌对奥希替尼的获得性耐药
DOI：
10.1016/j.taap.2019.114662
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发表时间：
2019-09-15
影响因子：
3.8
通讯作者：
Xu, Zhen-Ye
中科院分区：
文献类型：
--
作者：
Cao, Fei;Gong, Ya-Bin;Xu, Zhen-Ye
尽管奥希替尼（一种EGFR酪氨酸激酶抑制剂）已成为治疗EGFR激活突变的非小细胞肺癌（NSCLC）患者的标准疗法，但MCL-1的上调诱导了对奥希替尼的获得性耐药。蟾蜍灵是一种从传统中药蟾酥中分离出来的天然地高辛样成分，已被证明可以下调NSCLC细胞中的MCL-1。然而，蟾毒灵是否逆转NSCLC细胞对奥希替尼的这种获得性耐药性仍不清楚。在这项研究中，蟾蜍灵降低细胞活力，促进奥斯美替尼耐药细胞凋亡。此外，蟾蜍灵和奥希替尼联合治疗恢复了奥希替尼耐药细胞对奥希替尼诱导的体外和体内生长消退和细胞凋亡的敏感性。从机制上讲，MEK/ERK依赖性MCL-1磷酸化和Ku 70介导的MCL-1过表达赋予EGFR突变型NSCLC细胞奥希替尼耐药性。在奥西替尼耐药细胞中，蟾蜍灵调节Ku 70介导的MCL-1降解，但不调节MEK/ERK/MCL-1信号传导。总之，我们的研究表明蟾毒灵通过抑制Ku 70介导的MCL-1过表达消除了对奥希替尼的耐药性，表明奥希替尼和蟾毒灵的组合可能是克服NSCLC细胞对奥希替尼获得性耐药性的有效额外治疗。
Although osimertinib, an EGFR tyrosine kinase inhibitor, has become the standard therapy for treating non-small cell lung cancer (NSCLC) patients with EGFR-activating mutation, upregulation of MCL-1 induces acquired resistance to osimertinib. Bufalin, a natural digoxin-like ingredient isolated from a traditional Chinese medicine Chan Su, has been shown to downregulate MCL-1 in NSCLC cells. However, whether bufalin reverses this acquired resistance to osimertinib in NSCLC cells remains unclear. In this study, bufalin reduced cell viability and promoted apoptosis in osimertinib-resistant cells. Moreover, co-treatment with bufalin and osimertinib restored the sensitivity of osimertinib-resistant cells to osimertinib-induced growth regression and apoptosis in vitro and in vivo. Mechanistically, MEK/ERK-dependent MCL-1 phosphorylation and Ku70-mediated MCL-1 over expression confer osimertinib resistance in EGFR-mutant NSCLC cells. In osimertinib-resistant cells, bufalin modulates Ku70-mediated MCL-1 degradation, but not MEK/ERK/MCL-1 signaling. In conclusion, our study suggests that bufalin eliminates resistance to osimertinib by inhibiting Ku70-mediated MCL-1 overexpression, indicating that a combination of osimertinib and bufalin could be an effective additional treatment to overcome acquired resistance to osimertinib in NSCLC cells.