L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.

D Callegari,A J Mulholland,K E Ranaghan,M Mor,A Lodola,C J Woods,R Minari,M Tiseo

doi:10.1039/c7sc04761d

Abstract

Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step (i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR-osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.

Highlights

Epidermal growth factor receptor (EGFR) is a transmembrane protein which possesses an extracellular EGF binding domain and an intracellular tyrosine kinase domain.[1]
The clinical use of third-generation EGFR inhibitors is revealing the insurgence of novel mutations which confer to lung cancer cells the ability to escape EGFR inhibition
L718Q has emerged as an intriguing mutation considering that this occurs in a region of EGFR peripheral to the ATP binding site and that its effect is not obvious

Summary

Introduction

Epidermal growth factor receptor (EGFR) is a transmembrane protein which possesses an extracellular EGF binding domain and an intracellular tyrosine kinase domain.[1]. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys[797] alkylation and the free-energy of binding for the formation of the non-covalent complex.

Results

Conclusion