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

Cell Reports
Boris N Kholodenko

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.

References

May 13, 1999·Oncogene·C A Hall-JacksonP Cohen
Oct 9, 1999·The Journal of Biological Chemistry·B N KholodenkoJ B Hoek
Apr 8, 2000·Trends in Cell Biology·B N KholodenkoH V Westerhoff
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Jul 18, 2002·Nature Reviews. Drug Discovery·Margaret A Somerville
Dec 10, 2002·Science·G ManningS Sudarsanam
Jan 28, 2004·The Journal of Cell Biology·Nick I MarkevichBoris N Kholodenko
Mar 24, 2004·Cell·Paul T C WanUNKNOWN Cancer Genome Project
Feb 3, 2005·Nature Reviews. Drug Discovery·Curtis T KeithBrent R Stockwell
Mar 2, 2006·Molecular and Cellular Biology·Linda K RushworthWalter Kolch
May 16, 2006·Biophysical Journal·Jin YangJohn E Pearson
Jan 9, 2007·Biophysical Journal·Michael Ederer, Ernst Dieter Gilles
Feb 13, 2007·Nature Genetics·Roman K ThomasLevi A Garraway
May 16, 2009·Nature Reviews. Microbiology·Pamela J YehRoy Kishony
May 25, 2010·Nature Reviews. Molecular Cell Biology·Boris N KholodenkoWalter Kolch
Oct 23, 2012·Nature Chemical Biology·Likun WangDustin J Maly
Jan 29, 2013·Molecular Cell·Alyson K FreemanDeborah K Morrison
Mar 5, 2013·Annual Review of Biophysics·Ruth NussinovBuyong Ma
May 21, 2013·Nature Chemical Biology·Hugo LavoieMarc Therrien
Sep 3, 2013·Cell·Jiancheng HuAndrey S Shaw
Sep 10, 2013·The Journal of Biological Chemistry·Jennifer L Macdonald-ObermannLinda J Pike
Nov 10, 2013·Nature Medicine·Piro LitoDavid B Solit
Jan 7, 2014·Critical Reviews in Oncology/hematology·M A RahmanA K-Y Lam
May 17, 2014·Science·Andrew J BrooksMichael J Waters
Jun 16, 2014·Nature Cell Biology·David RomanoWalter Kolch
Jun 25, 2014·Nature Reviews. Cancer·Matthew HolderfieldMartin McMahon
Sep 16, 2014·Trends in Biochemical Sciences·Hugo LavoieFrank Sicheri
Apr 25, 2015·Nature Reviews. Molecular Cell Biology·Hugo Lavoie, Marc Therrien

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Citations

Jun 29, 2016·Seminars in Cell & Developmental Biology·Dirk FeyBoris N Kholodenko
Mar 24, 2017·Expert Opinion on Therapeutic Targets·Beth K NeilsenKurt W Fisher
Nov 28, 2017·Molecular Systems Biology·Benjamin M GyoriPeter K Sorger
Apr 10, 2020·Oncogene·Tilman Brummer, Campbell McInnes
Sep 1, 2018·Science·Walter Kolch, Christina Kiel
Sep 27, 2018·Nature Communications·Eshan D MitraWilliam S Hlavacek
Feb 13, 2020·International Journal of Molecular Sciences·Shannon LeeWalter Kolch
Oct 31, 2020·Current Opinion in Structural Biology·Oleksii RukhlenkoWalter Kolch
Mar 9, 2018·Seminars in Cancer Biology·Keesha E EricksonBoris N Kholodenko
May 27, 2021·Cell Reports·Boris N KholodenkoOleksii S Rukhlenko

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