Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

Abstract

Epidermal growth factor receptor (EGFR) targeted therapy is one of the most important and effective strategies to combat EGFR mutant nonsmall-cell lung cancer (NSCLC). However, a substantial number of patients bearing EGFR exon 20 insertion (Ex20ins) mutations respond poorly to common EGFR targeted therapies. This clinical need remained unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib was approved by the FDA. Despite this progress, the structural mechanisms of EGFR Ex20ins mutation resistance and characterization of inhibitor binding modes have not been systematically summarized. Herein, we analyze the structural mechanisms for ligand binding and resistance and summarize recent developments for the reported inhibitors of EGFR Ex20ins mutations. Furthermore, this Perspective aims to provide insights for the design of the next generation of EGFR Ex20ins inhibitors.

The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

“…Previous studies have shown that researchers create appropriate drugs for different mutations based on homology modeling and simulation experiments ( 103 ). In future work, focus should be placed on exploring structural changes to determine which mutation sites render patients more sensitive to EGFR TKIs, whether accompanied by alterations in other pathways, to provide a basis for prognosis assessment and drug decision-making ( 104 ).…”