Systematic profiling of ATP response to acquired drug-resistant EGFR family kinase mutations

Dingwa Zhang, Deyong He, Xiaoliang Pan, Lijun Liu

Abstract


Kinase-targeted cancer therapy (KTCT) with ATP-competitive inhi­bitors has been widely applied in clinics. However, a number of kinase mis­sense mutations were observed to confer acquired drug resistance during ther­apy, largely limiting the clinical application of kinase inhibitors in KTCT. Ins­tead of directly influencing inhibitor binding, kinase mutations can also cause generic resistance to ATP-competitive inhibitors by increasing ATP affinity. Herein, the intermolecular interaction of the ATP molecule with clinically observed drug-resistant EGFR family kinase mutations involved in human can­cer are systematically characterize. Rigorous quantum mechanics/molecular mechanics (QM/MM) calculation and empirical Poisson–Boltzmann/surface area (PB/SA) analysis as well as in vitro kinase assay and surface plasmon resonance analysis were integrated to explore the binding capability of ATP to mutant residues in the structural context of the kinase domain, which resulted in a comprehensive profile of ATP response to acquired drug-resistant mutat­ions of four EGFR family kinases (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4). From the profile, it was possible to identify those potent mutations that may influence ATP binding significantly; such mutations are potential candidates to cause generic resistance for ATP-competitive inhibitors. Consequently, the well documented generic drug-resistant mutation EGFR T790M and its count­erpart ErbB2 T798M are found to increase ATP affinity by establishing an additional S–π interaction between the side-chain thioether group of the mutant Met residue and the aromatic adenine moiety of the ATP molecule, while EGFR D761Y is identified as a new generic drug-resistant mutation that can increase ATP affinity by eliminating unfavorable electrostatic repulsion. In contrast, ErbB2 K753E and T768I are considered to be two generic drug-sen­sitive mutations that can decrease ATP affinity by unfavorable charge reversal and by impairing favorable polar interaction, respectively. In addition, the EGFR L858R mutation is located at the kinase activation loop and nearby the kinase active site, thus largely complicating the multiply dependent relat­ion­ship of kinase, ATP and inhibitor, which therefore exhibits divergent effects on different tested inhibitors.


Keywords


molecular modeling; inhibitor; biomolecular interaction; missense mutation; human cancer

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DOI: https://doi.org/10.2298/JSC191124028Z

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