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Review
. 2018 Nov 15;7(11):212.
doi: 10.3390/cells7110212.

Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Tatsuya Nagano  1 , Motoko Tachihara  2 , Yoshihiro Nishimura  3
Affiliations
Review

Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Tatsuya Nagano et al. Cells. .

Abstract

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib-a third-generation EGFR-TKI-targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial⁻mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.

Keywords: C797S; T790M; acquired resistance; alternative pathway; primary resistance; transformation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of acquired resistance to first-generation tyrosine kinase inhibitors (gefitinib and erlotinib) [15,16]. EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; MET, mesenchymal–epithelial transition factor; EMT, epithelial–mesenchymal transition; SCLC, small-cell lung cancer.
Figure 2
Figure 2
Mechanisms of acquired resistance to osimertinib [32,33,34,35,36]. EGFR, epidermal growth factor receptor; MET, mesenchymal-epithelial transition factor; HER2, human epidermal growth factor receptor 2; FGFR1, fibroblast growth factor receptor 1; KRAS, Kirsten rat sarcoma viral oncogene homolog; PIK3CA, phosphoinositide-3-kinase P110α catalytic subunit; SCLC, small-cell lung cancer.
Figure 3
Figure 3
The downstream signaling of the epidermal growth factor receptor.
See this image and copyright information in PMC

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