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

• Allosteric kinase activation caused by dimerization conveys drug resistance
• Thermodynamic factors account for paradoxical kinase activation by a drug
• Accumulation of dimers harboring drug-bound and free protomers drives resistance
• Two inhibitors, ineffective on their own, when combined can abolish drug resistance

SummaryTreatment 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.

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