Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
Pharmacol Res. 2022 Jan;175:105998. doi: 10.1016/j.phrs.2021.105998. Epub 2021 Nov 24.
Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when combined with osimertinib, synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.
小檗碱是一种天然产物，由于其具有抗菌、抗炎和代谢调节特性，长期以来一直被用于传统中药。奥希替尼是第一种用于治疗具有激活 EGFR 突变和因 T790M 突变而对第一代 EGFR-TKI 耐药的非小细胞肺癌（NSCLC）的第三代 EGFR 酪氨酸激酶抑制剂（TKI）。然而，奥希替尼获得性耐药的出现限制了其在临床上的长期疗效。奥希替尼和其他 EGFR-TKI 获得性耐药的一个已知机制是 MET（c-MET）基因扩增。在这里，我们报告小檗碱与奥希替尼联合使用时，协同且选择性地降低了几种 MET 扩增的奥希替尼耐药 EGFR 突变 NSCLC 细胞系的存活，增强了细胞凋亡的诱导，可能是通过 Bim 上调和 Mcl-1 下调。重要的是，这种组合有效地增强了对裸鼠中 MET 扩增的奥希替尼耐药异种移植物生长的抑制作用，且耐受性良好。分子建模表明，小檗碱能够与非磷酸化 MET 的激酶结构域结合，占据结合口袋的前面，并与激活环相互作用，其方式与其他已知的 MET 抑制剂相似。MET 激酶测定显示小檗碱对 MET 活性具有明显的浓度依赖性抑制作用，证实了其激酶抑制活性。这些发现共同表明，小檗碱可以作为一种天然存在的 MET 抑制剂，与奥希替尼协同作用，克服由 MET 扩增引起的奥希替尼获得性耐药。
