Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects

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Title: Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric Inhibitor Effects
Authors: Kholodenko, Boris N.
Permanent link: http://hdl.handle.net/10197/9777
Date: 22-Sep-2015
Online since: 2019-04-03T07:41:34Z
Abstract: 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.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Type of material: Journal Article
Publisher: Cell Press
Journal: Cell Reports
Volume: 12
Start page: 1939
End page: 1949
Copyright (published version): 2015 the Author
Keywords: Allosteric Inhibitor EffectsAllosteric kinase activationdrug-facilitated dimerizationBRAFCRAFDrug resistanceKinase dimerizationAllosteric inhibitor effects
DOI: 10.1016/j.celrep.2015.08.014
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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