Tuberc Respir Dis.  2016 Oct;79(4):248-256. 10.4046/trd.2016.79.4.248.

Mechanisms of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance and Strategies to Overcome Resistance in Lung Adenocarcinoma

• Chang YS
• Choi CM
• Lee JC

• KMID: 2365316
• DOI: http://doi.org/10.4046/trd.2016.79.4.248

Abstract

Somatic mutations that lead to hyperactivation of epidermal growth factor receptor (EGFR) signaling are detected in approximately 50% of lung adenocarcinoma in people from the Far East population and tyrosine kinase inhibitors are now the standard first line treatment for advanced disease. They have led to a doubling of progression-free survival and an increase in overall survival by more than 2 years. However, emergence of resistant clones has become the primary cause for treatment failure, and has created a new challenge in the daily management of patients with EGFR mutations. Identification of mechanisms leading to inhibitor resistance has led to new therapeutic modalities, some of which have now been adapted for patients with unsuccessful tyrosine kinase inhibitor treatment. In this review, we describe mechanisms of tyrosine kinase inhibitor resistance and the available strategies to overcoming resistance.

Keyword

Drug Resistance; Receptor, Epidermal Growth Factor; Adenocarcinoma of Lung; Genes, erbB-1

MeSH Terms

Adenocarcinoma*
Clone Cells
Disease-Free Survival
Drug Resistance
Epidermal Growth Factor*
Far East
Genes, erbB-1
Humans
Lung*
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor*
Treatment Failure
Epidermal Growth Factor
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor

Figure

• 

  Figure 1 Resistance mechanism against first generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). (A) Mutations in the EGFR gene. T790M mutation induces conformational changes on the ATP-binding pocket of EGFR–tyrosine kinase domain, inhibiting interaction with the drug target site. (B) Activation of alternative signaling pathways. MET amplification, and overexpression of phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), and AXL bypass the dependency on EGFR activation and can promote survival and proliferation. (C) Phenotypic changes, small cell lung cancer transformation, and epithelial-mesenchymal transition (EMT) confer resistance to EGFR-TKI. SCLC: small cell lung cancer.

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