Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.
Highlights
Genotype-directed molecular-targeted therapies are the standard of care for a subset of lung cancers that harbor an activated oncogene with a driver mutation [1]
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as first-generation gefitinib and erlotinib, second-generation afatinib and dacomitinib, and third-generation osimertinib are available in clinical practice for patients with EGFRsensitizing mutations, which account for ≈90% of all EGFR-activating mutations
When we examined the effects of drug concentrations on the inducibility of the drug-tolerant cells (DTCs) phenotype, we found that higher concentrations of afatinib (>180 nM) induced the DTC phenotype and that lower concentrations of osimertinib (
Summary
Genotype-directed molecular-targeted therapies are the standard of care for a subset of lung cancers that harbor an activated oncogene with a driver mutation [1]. EGFR tyrosine kinase inhibitors (TKIs) such as first-generation gefitinib and erlotinib, second-generation afatinib and dacomitinib, and third-generation osimertinib are available in clinical practice for patients with EGFRsensitizing mutations, which account for ≈90% of all EGFR-activating mutations. These EGFR TKIs are administered as monotherapy or, in the case of erlotinib or gefitinib, in combination with a fully humanized anti-VEGFR monoclonal antibody (ramucirumab). We observe in our daily clinical practice that almost all patients eventually progress, including those who experience a complete remission These facts indicate that some cancer cells are still viable after exposure to EGFR TKIs
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