C797S Resistance: The Undruggable EGFR Mutation in Non-Small Cell Lung Cancer?

Abstract

The first evidence of osimertinib resistance mediated by the epidermal growth factor receptor (EGFR) mutation C797S was reported three years ago. Since then, no major breakthroughs have been achieved to target the clinically relevant mutant variant that impedes covalent bond formation with irreversible EGFR inhibitors. Although several biochemically active compounds have been described, only a few inhibitors that potently act on the cellular level or in vivo have been introduced so far. Herein, we give an overview of current approaches in the field and highlight the challenges that need to be addressed in future research projects to overcome the C797S-mediated drug resistance.

Figure 1

(A) Chemical structures of first, second, and third generation EGFR inhibitors. The acrylamide warhead is highlighted in yellow. (B) Structural analysis of EGFR-C797S that impedes covalent bond formation with irreversible inhibitors (model based on PDB IDs: 3IKA, 5X2K). The QR-code provides an augmented reality view of a 3D model of the binding site.

Figure 2

Binding modes and chemical structures of inhibitors targeting the C797S mutant EGFR. (A) Aminopyrimidine-based ALK and EGFR/ALK dual inhibitors 3–6. Interactions with the catalytic lysine are highlighted in yellow (PDB ID: 5GTZ). (B) Aminopyridinyl imidazole-based inhibitors 7–8. Interaction with the phosphate binding site is highlighted in orange (covalent docking results). (C) Aminopurine-based inhibitor 9. Interaction with the hydrophobic clamp motif is highlighted in green (PDB ID: 5X2C). (D) Phenol-based inhibitor 10 identified through virtual screening. Interaction with the Ser797 side chain is highlighted in red (docking results). (E) Allosteric inhibitor 11 occupies an allosteric binding site, highlighted in blue (PDB ID: 5D41).