Abstract
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK.
Highlights
Lung cancer is the leading cause of cancer death worldwide
The expression of echinoderm microtubule-associated protein–like 4 gene (EML4)-anaplastic lymphoma kinase gene (ALK) was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells
Fusion of the echinoderm microtubule-associated protein–like 4 gene (EML4) with the anaplastic lymphoma kinase gene (ALK), which results in the production of a fusion protein (EML4-ALK), occurs in 5% to 10% of cases of non–small cell lung cancer (NSCLC; refs. 1–3)
Summary
Lung cancer is the leading cause of cancer death worldwide. Fusion of the echinoderm microtubule-associated protein–like 4 gene (EML4) with the anaplastic lymphoma kinase gene (ALK), which results in the production of a fusion protein (EML4-ALK), occurs in 5% to 10% of cases of non–small cell lung cancer (NSCLC; refs. 1–3). Fusion of the echinoderm microtubule-associated protein–like 4 gene (EML4) with the anaplastic lymphoma kinase gene (ALK), which results in the production of a fusion protein (EML4-ALK), occurs in 5% to 10% of cases of non–small cell lung cancer Marked antitumor effects in NSCLC positive for EML4-ALK in both preclinical and clinical studies [4]. Despite their initial response, individuals with EML4-ALK–positive NSCLC treated with ALK inhibitors eventually acquire resistance to these drugs [5], and the molecular mechanisms responsible for such resistance remain largely uncharacterized. With the use of an in vitro cell model and cells newly derived from a patient with acquired resistance to the ALK inhibitor crizotinib, we have uncovered a previously unknown mechanism of such resistance
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