Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw’s measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC50 = 382 nM vs. IC50 = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC50 = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC50 = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and MET G1163R mutations that are also resistant to crizotinib treatment in NSCLC.
Highlights
IntroductionMutation L1198F, located near the ATP/inhibitor-binding site, enhances the sensitivity to crizotinib, achieving an IC50 = 0.4 nM compared with the WT’s IC50 = 20 nM as measured by Shaw et al.[22]
(IC50 = 130 nM), are adjacent to the ATP/inhibitor-binding site in the kinase domain, cause steric hindrance to the inhibitors, but enable resumption of Anaplastic lymphoma kinase (ALK) activity[21]
The ALK G1202R is analogous to the MET G1163R and ROS1 G2302R mutations that are notorious for crizotinib resistance in NSCLC49,50
Summary
Mutation L1198F, located near the ATP/inhibitor-binding site, enhances the sensitivity to crizotinib, achieving an IC50 = 0.4 nM compared with the WT’s IC50 = 20 nM as measured by Shaw et al.[22]. The binding affinity of crizotinib in G1202R mutant should be better than that in WT and this introduces a conflict in the observed drug resistance by G1202R replacement. To resolve this conflict, we performed molecular dynamics (MD) simulations on the apo WT, G1202R mutant, L1198F mutant, and L1198F/G1202R mutant to investigate the minute conformation variance near the crizotinib binding pocket entrance so that we could correlate the observed drug accessibility to the varied IC50 values. On the basis of the obtained kinetic and thermodynamic observations, we provided valuable information applicable to drug development of ALK inhibitors
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