The next tier of EGFR resistance mutations in lung cancer

Oncogene. 2021 Jan;40(1):1-11. doi: 10.1038/s41388-020-01510-w. Epub 2020 Oct 15.


EGFR mutations account for the majority of druggable targets in lung adenocarcinoma. Over the past decades the optimization of EGFR inhibitors revolutionized the treatment options for patients suffering from this disease. The pace of this development was largely dictated by the inevitable emergence of resistance mutations during drug treatment. As a result, a rapid understanding of the structural and molecular biology of the individual mutations is the key for the development of next-generation inhibitors. Currently, the field faces an unprecedented number of combinations of activating mutations with distinct resistance mutations in parallel to the approval of osimertinib as a first-line drug for EGFR-mutant lung cancer. In this review, we present a survey of the diverse landscape of EGFR resistance mechanisms with a focus on new insights into on-target EGFR kinase mutations. We discuss array of mutations, their structural effects on the EGFR kinase domain as well as the most promising strategies to overcome the individual resistance profiles found in lung cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics*
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / chemistry
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Models, Molecular
  • Mutation*
  • Protein Conformation
  • Protein Domains
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use


  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors