title: Insight on Mutation-Induced Resistance from Molecular Dynamics Simulations of the Native and Mutated CSF-1R and KIT.
abstract: The receptors tyrosine kinases (RTKs) for the colony stimulating factor-1, CSF-1R, and for the stem cell factor, SCFR or KIT, are important mediators of signal transduction. The abnormal function of these receptors, promoted by gain-of-function mutations, leads to their constitutive activation, associated with cancer or other proliferative diseases. A secondary effect of the mutations is the alteration of receptors' sensitivity to tyrosine kinase inhibitors, compromising effectiveness of these molecules in clinical treatment. In particular, the mutation V560G in KIT increases its sensitivity to Imatinib, while the D816V in KIT, and D802V in CSF-1R, triggers resistance to the drug. We analyzed the Imatinib binding affinity to the native and mutated KIT (mutations V560G, S628N and D816V) and CSF-1R (mutation D802V) by using molecular dynamics simulations and energy calculations of Imatinib•target complexes. Further, we evaluated the sensitivity of the studied KIT receptors to Imatinib by measuring the inhibition of KIT phosphorylation. Our study showed that (i) the binding free energy of Imatinib to the targets is highly correlated with their experimentally measured sensitivity; (ii) the electrostatic interactions are a decisive factor affecting the binding energy; (iii) the most deleterious impact to the Imatinib sensitivity is promoted by D802V (CSF-1R) and D816V (KIT) mutations; (iv) the role of the juxtamembrane region, JMR, in the imatinib binding is accessory. These findings contribute to a better description of the mutation-induced effects alternating the targets sensitivity to Imatinib.
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée (LBPA), ENS Cachan, CNRS, Université, Paris-Saclay, 94235 Cachan, France.|Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro, 373 av. Carlos Chagas Filho, 21941-902, Rio de Janeiro, Brazil.
authors.forename: Priscila
authors.initials: P
authors.lastname: Da Silva Figueiredo Celestino Gomes
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée (LBPA), ENS Cachan, CNRS, Université, Paris-Saclay, 94235 Cachan, France.
authors.forename: Isaure
authors.initials: I
authors.lastname: Chauvot De Beauchêne
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée (LBPA), ENS Cachan, CNRS, Université, Paris-Saclay, 94235 Cachan, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Panel
authors.affiliation: INSERM U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lopez
authors.affiliation: INSERM U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France.
authors.forename: Paulo
authors.initials: P
authors.lastname: De Sepulveda
authors.affiliation: Laboratório de Modelagem e Dinâmica Molecular, Instituto de Biofísica Carlos Chagas FilhoUniversidade Federal do Rio de Janeiro, 373 av. Carlos Chagas Filho, 21941-902, Rio de Janeiro, Brazil.
authors.forename: Pedro
authors.initials: P
authors.lastname: Geraldo Pascutti
authors.affiliation: Inserm UMR1170, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif cedex, France.|Paris-Sud University, Faculty of Medicine, Le Kremlin-Bicêtre, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée (LBPA), ENS Cachan, CNRS, Université, Paris-Saclay, 94235 Cachan, France.|Centre de Mathématiques et de Leurs Applications, (CMLA), ENS Cachan, CNRS, Université, Paris-Saclay, 94235 Cachan, France.
authors.forename: Luba
authors.initials: L
authors.lastname: Tchertanov
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D016186:Receptor, Macrophage Colony-Stimulating Factor