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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Drug Resistance Resulting from Kinase Dimerization Is Rationalized by Thermodynamic Factors Describing Allosteric

Boris N Kholodenko1

  • 1Systems 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 Reports
|September 8, 2015
PubMed

Insights

Drug resistance in cancer kinase inhibitors can be overcome using thermodynamic principles. Combining two inhibitors can abolish resistance at lower doses than single agents, suggesting new therapeutic strategies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • ATP-competitive inhibitors of BRAF/CRAF kinases paradoxically increase kinase activity in cancer patients, leading to treatment resistance.
  • Kinase inhibition resistance is common and linked to homo/heterodimerization in kinase activation cycles.

Purpose of the Study:

  • To explain drug resistance in kinases due to dimerization using thermodynamic principles.
  • To develop mechanistic models for overcoming kinase inhibitor resistance.

Main Methods:

  • Applied thermodynamic principles to analyze allosteric regulation by kinase inhibitors.
  • Quantified inhibitor-induced changes in kinase dimerization and drug affinity for monomers versus dimers.
  • Extended analysis to homo- and heterodimers, including symmetric and asymmetric conformations.

Main Results:

  • Thermodynamic factors were identified that describe inhibitor-induced changes in kinase dimerization.
  • Dose-response dependencies were predicted based on thermodynamic factors influencing dimerization.
  • Combined inhibition with two drugs abolished resistance at lower doses than monotherapy.

Conclusions:

  • Kinase dimerization is a key factor in drug resistance, explainable by thermodynamics.
  • Mechanistic models provide insights into overcoming resistance to kinase inhibitors.
  • Combination therapy strategies can be optimized using thermodynamic principles to enhance efficacy.

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