Computational analysis of ABL kinase mutations allows predicting drug sensitivity against selective kinase inhibitors

Abstract

The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients. Initial validation analysis of our approach using a panel of previously studied frequent mutations indicated that the computational data generated in this study correlated well with the published experimental/clinical data. In addition, we present drug sensitivity profiles for remaining point mutations by computational docking analysis using imatinib as well as next generation ABL inhibitors nilotinib, dasatinib, bosutinib, axitinib, and ponatinib. Our results indicate distinct drug sensitivity profiles for ABL mutants toward kinase inhibitors. In addition, drug sensitivity profiles of a set of compound mutations in ABL kinase were also presented in this study. Thus, our large scale computational study provides comprehensive sensitivity/resistance profiles of ABL mutations toward specific kinase inhibitors.

Mutation Profiling of BCR-ABL Kinase Domain in Chronic Myeloid Leukaemia Patients with Imatinib Resistance

“…However, we identi ed K357T mutation which involved a substitution from Lysine (K) to Threonine (T) (AAA→ACA). According to Kamasani and colleagues (2017), they noted K285N involving a substitution from Lysine (K) to Asparagine (N) and K285R involving a substitution from Lysine (K) to Arginine (R) instead of K285I that we identi ed in this study involving a substitution from Lysine (K) to Isoleucine (I) (AAA→ATA) [14].…”

Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase

“…Three imatinib resistance mutations were selected (Fig. 1A) with the following criteria in mind: 1) they are major resistance mutations found in patients; 2) they are from the subset of the 15 dynamic hot spots; and 3) their mechanism is not understood, with either controversial or inconclusive prior literature studies (19,20,25,26). F317L is located at the back of the P loop, and the phenylalanine was suggested to be important for van der Waals interactions and polar stacking with the aromatic ring of imatinib (21,24,(27)(28)(29)(30).…”

Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer

“…Several computational studies have investigated the impact of protein mutations on drug efficacy ( Kamasani et al., 2017 , Martínez-Jiménez et al., 2017 , Paul et al., 2016 , Reeve et al., 2015 ), mainly in an antiviral or antibacterial context ( Frey et al., 2010 , Hosseini et al., 2016 , Fowler et al., 2018 ). However, rarely do these studies prospectively identify drug resistance mutations ( Frey et al., 2010 , Paul et al., 2016 , Reeve et al., 2015 ).…”