Kholodenko Boris N
Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Cell Rep. 2015 Sep 22;12(11):1939-49. doi: 10.1016/j.celrep.2015.08.014. Epub 2015 Sep 3.
Treatment of cancer patients with ATP-competitive inhibitors of BRAF/CRAF kinases surprisingly increases total kinase activity, especially in wild-type BRAF cells, subverting the desired clinical outcome. Similar inhibition resistance is observed for numerous kinases involving homo/heterodimerization in their activation cycles. Here, I demonstrate that drug resistance resulting from kinase dimerization can be explained using thermodynamic principles. I show that allosteric regulation by inhibitors is described by thermodynamic factors that quantify inhibitor-induced changes in kinase dimerization and the difference in the drug affinity for a free monomer versus a dimer harboring one drug molecule. The analysis extends to kinase homo- and heterodimers, allows for their symmetric and asymmetric conformations, and predicts how thermodynamic factors influence dose-response dependencies. I show how two inhibitors, ineffective on their own, when combined can abolish drug resistance at lower doses than either inhibitor applied alone. Thus, the mechanistic models suggest ways to overcome resistance to kinase inhibitors.
用BRAF/CRAF激酶的ATP竞争性抑制剂治疗癌症患者，令人惊讶的是会增加总激酶活性，尤其是在野生型BRAF细胞中，从而颠覆了预期的临床结果。对于许多在其激活周期中涉及同/异二聚化的激酶，也观察到类似的抑制抗性。在此，我证明了激酶二聚化导致的耐药性可以用热力学原理来解释。我表明，抑制剂的变构调节由热力学因素描述，这些因素量化了抑制剂诱导的激酶二聚化变化以及药物对游离单体与含有一个药物分子的二聚体的亲和力差异。该分析扩展到激酶同二聚体和异二聚体，考虑了它们的对称和不对称构象，并预测了热力学因素如何影响剂量反应依赖性。我展示了两种单独无效的抑制剂联合使用时，如何能以比单独使用任何一种抑制剂更低的剂量消除耐药性。因此，这些机制模型提出了克服激酶抑制剂耐药性的方法。
