Department of Oncology, the First Affiliated Hospital of Xinxiang Medical University, 88 JianKang Road, Xinxiang 453003, China.
Department of Oncology, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Shanghai 200437, China.
Toxicol Appl Pharmacol. 2019 Sep 15;379:114662. doi: 10.1016/j.taap.2019.114662. Epub 2019 Jul 10.
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 overexpression 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.
虽然表皮生长因子受体酪氨酸激酶抑制剂奥希替尼已成为治疗表皮生长因子受体激活突变的非小细胞肺癌（NSCLC）患者的标准疗法，但 MCL-1 的上调会导致奥希替尼获得性耐药。蟾毒灵是从一种传统中药蟾酥中分离出的一种天然洋地黄样成分，已被证明可下调 NSCLC 细胞中的 MCL-1。然而，蟾毒灵是否能逆转 NSCLC 细胞对奥希替尼的这种获得性耐药仍不清楚。在这项研究中，蟾毒灵降低了奥希替尼耐药细胞的活力并促进了其凋亡。此外，蟾毒灵与奥希替尼联合治疗可恢复奥希替尼耐药细胞对奥希替尼诱导的生长抑制和凋亡的敏感性，无论是在体外还是体内。从机制上讲，MEK/ERK 依赖性 MCL-1 磷酸化和 Ku70 介导的 MCL-1 过表达赋予 EGFR 突变型 NSCLC 细胞对奥希替尼的耐药性。在奥希替尼耐药细胞中，蟾毒灵调节 Ku70 介导的 MCL-1 降解，但不调节 MEK/ERK/MCL-1 信号。总之，我们的研究表明，蟾毒灵通过抑制 Ku70 介导的 MCL-1 过表达来消除对奥希替尼的耐药性，表明奥希替尼联合蟾毒灵可能是克服 NSCLC 细胞奥希替尼获得性耐药的有效附加治疗方法。
