Insight into ponatinib resistance mechanisms in rhabdomyosarcoma caused by the mutations in FGFR4 tyrosine kinase using molecular modeling strategies
Insight into ponatinib resistance mechanisms in rhabdomyosarcoma caused by the mutations in FGFR4 tyrosine kinase using molecular modeling strategies
复制标题
使用分子建模策略深入了解 FGFR4 酪氨酸激酶突变引起的横纹肌肉瘤中的帕纳替尼耐药机制
DOI：
10.1016/j.ijbiomac.2019.05.138
复制
发表时间：
2019
影响因子：
8.2
通讯作者：
Cai Yuepiao
中科院分区：
文献类型：
--
作者：
Wu Chao;Chen Xiaolu;Chen Daoxing;Xia Qinqin;Liu Zhiguo;Li Fuchuan;Yan Yuxiang;Cai Yuepiao
新的有效的治疗横纹肌肉瘤（RMS）的低毒性尚未出现。RMS的基因组分析报道，受体酪氨酸激酶FGFR4在肿瘤组织中高度表达并经常发生突变。RMS中FGFR4的V550E/L和N535D/K突变可导致对几乎所有i型抑制剂的强耐药性。先前的报告表明，ii型抑制剂ponatinib是RMS最有效的药物，但仍然难以右舷V550E/L突变体。在这种情况下，采用一系列分子建模策略从理论上揭示抗性机制。各种策略预测的结合自由能计算结果表明，V550E/L突变确实削弱了ponatinib的结合亲和力，而不是N535D/K突变，这与实验观察结果吻合较好。随后，能量分解分析绘制了一些关键残留物的不同能量成分的连锁效应。此外，报告ii型抑制剂沿着a环滑动以阻止FGFR4磷酸化和激活的有效通道是非常重要的。我们的研究结果为药物结合过程提供了新的见解，并指导开发有效的抑制剂来克服RMS的耐药性。
Novel efficacious treatment of Rhabdomyosarcoma (RMS) with less toxicity has yet to emerge. Genomic analysis of RMS has reported that the receptor tyrosine kinase FGFR4 is highly expressed and frequently mutated in the tumor tissue. The V550E/L and N535D/K mutations of FGFR4 in RMS can lead to strong drug resistance to almost all of the type-I inhibitors. Previous report has demonstrated the type-II inhibitor ponatinib is the most potentially effective agent for RMS but still hard to starboard the V550E/L mutants. In this case, an ensemble of molecular modeling strategies was employed to theoretically uncover the resistance mechanisms. The binding free energy calculation results predicted by various strategies show that the V550E/L rather than N535D/K mutations indeed weaken the binding affinity of ponatinib, which are in good agreement with the experimental observations. Subsequently, the energy decomposition analysis mapped a knock-on effect on the diverse energy components of some key residues. Moreover, it is of great importance to report that there is an effective channel for type-II inhibitors sliding along the A-loop to prevent FGFR4 from phosphorylation and activation. Our results provide new insight into drug binding process and guide the development of effective inhibitors to surmount drug resistance in RMS.