Abstract
Second- and third-generation inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity (EGFR-TKIs) are improving the treatment of patients with non-small cell lung cancer. Here we established two sublines (BR1-8 and BR2-3) resistant to a second-generation inhibitor, afatinib, from the human lung cancer cell line HCC827 that harbors a mutation that activates the tyrosine kinase activity of EGFR. These afatinib-resistant sublines were resistant to first-generation EGFR-TKIs, gefitinib and erlotinib, and a third-generation EGFR-TKI, osimertinib. These resistant sublines showed markedly reduced levels of multiple EGFR family proteins, including the activated mutant EGFR, and complete loss of EGFR amplification as compared with their parental HCC827 cells harboring amplification of EGFR gene. Treatment with the multikinase inhibitor dasatinib or transfection with a SRC small interfering RNA inhibited cell survival and AKT phosphorylation in drug-resistant sublines to a greater extent compared with HCC827 cells. Further, the migration of drug-resistant cells was greater compared with that of HCC827 cells and was inhibited by dasatinib or an FAK inhibitor. These findings indicate that compensatory activation of SRC family kinases (SFKs) and FAK supports the survival and migration of afatinib-resistant cells when the expression of multiple EGFR family proteins was mostly abrogated. Combinations of potent drugs that target SFKs and FAK may overcome the resistance of lung cancer cells to second-generation TKIs.
Highlights
Somatic mutations in the epidermal growth factor receptor (EGFR) gene that activate EGFR tyrosine kinase activity are major determinants of the clinical efficacy of firstgeneration EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib that are used to treat patients with nonsmall cell lung cancer (NSCLC) [1,2,3,4,5]
We established two afatinib-resistant sublines, HCC827/BR1-8 (BR1-8) and HCC827/BR2-3 (BR2-3), after exposing the parental lung cancer cell line HCC827, which harbors a mutation of EGFR exon 19 (E746-A750) that activates tyrosine kinase activity, to step-wise increasing concentrations of afatinib up to 1 μmol/L
HCC827 cells harboring an activating EGFR mutation are highly susceptible to EGFR-TKIs, and the afatinib-resistant sublines derived here from HCC827 cells showed the characteristics as follows: (1) The levels of EGFR, an activated mutant EGFR, HER2, HER3, HER4, MET, and PDGFRβ were reduced compared with those of the parental cells, and EGFR amplification was lost
Summary
Somatic mutations in the epidermal growth factor receptor (EGFR) gene that activate EGFR tyrosine kinase activity are major determinants of the clinical efficacy of firstgeneration EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib that are used to treat patients with nonsmall cell lung cancer (NSCLC) [1,2,3,4,5]. Treatment with EGFRTKIs benefits most patients with NSCLC with activating EGFR mutations, their final clinical efficacy varies, because tumors develop resistance [6]. Targeting EGFR and its family members using a combination of afatinib and cetuximab achieved improved therapeutic efficacies against acquired drug-resistant lung cancers with or without the EGFR T790M mutation [19]. The irreversible third-generation EGFR-TKI osimertinib that targets EGFR T790M shows promising responses against an activated mutant EGFR with a T790M mutation in a tumor xenograft model as well as in a clinical trial [21]. The therapeutic efficacy of osimertinib is expected to provide benefits against EGFR T790Mdriven acquired drug-resistant tumors [6]. Osimertinib is highly active in patients with lung cancer with the EGFR T790M mutation who experience disease progression during prior therapy using EGFR-TKIs [22]
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