Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas

Alexis B Cortot, Pasi A Jänne, Alexis B Cortot, Pasi A Jänne

Abstract

The discovery of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has allowed the identification of a subset of patients whose tumours are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). Despite the efficacy and superiority of EGFR TKIs over chemotherapy as first-line therapy, all patients will ultimately develop progressive disease, with a median of 9-13 months progression-free survival. A better understanding of the molecular mechanisms underlying resistance to EGFR TKIs can help design new drugs and therapeutic strategies to overcome resistance. This has been illustrated by the new generation TKIs that are effective on the T790M mutation, which is the most frequent mechanism of acquired resistance to EGFR TKIs. In this article, we will address the main molecular mechanisms of primary and acquired resistance to EGFR TKIs in EGFR-mutant NSCLC.

Conflict of interest statement

Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com

©ERS 2014.

Figures

Figure 1.
Figure 1.
Main mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR-mutant nonsmall cell lung cancer. SCLC: small cell lung cancer; EMT: epithelial–mesenchymal transition.
Figure 2.
Figure 2.
Gefitinib dissociation constants and Michaelis–Menten constants for the wild type and mutant epidermal growth factor receptor kinases. Data from [60].

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