Exon 16-Skipping HER2 as a Novel Mechanism of Osimertinib Resistance in EGFR L858R/T790M-Positive Non-Small Cell Lung Cancer
Journal
Journal of Thoracic Oncology
Journal Volume
15
Journal Issue
1
Pages
50-61
Date Issued
2020
Author(s)
Abstract
Introduction: Osimertinib is the current recommended treatment for EGFR T790M–positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/T790M–positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell–free DNA analysis revealed the occurrence of exon 16–skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinib-resistant mechanism. Methods: We constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method. Results: We found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed to reverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells. Conclusion: HER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer. ? 2019 International Association for the Study of Lung Cancer
SDGs
Other Subjects
afatinib; cisplatin; dasatinib; docetaxel; epidermal growth factor receptor; epidermal growth factor receptor 2; erlotinib; gefitinib; gemcitabine; osimertinib; paclitaxel; pemetrexed; vinorelbine tartrate; acrylamide derivative; aniline derivative; EGFR protein, human; epidermal growth factor receptor; osimertinib; protein kinase inhibitor; adult; Article; cancer growth; case report; cell culture; cell viability; clinical article; computer assisted tomography; controlled study; drug effect; drug fatality; EGFR gene; exon; gene expression; gene function; genetic transfection; HER2 gene; HER2D16 gene; human; human cell; immunoprecipitation; male; malignant pleura effusion; middle aged; NCI-H1975 cell line; next generation sequencing; non small cell lung cancer; oncogene; phase 1 clinical trial; pneumonia; polyacrylamide gel electrophoresis; polymerase chain reaction; priority journal; radiofrequency ablation; signal transduction; treatment duration; treatment failure; Western blotting; drug resistance; exon; genetics; lung tumor; mutation; non small cell lung cancer; Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Exons; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
Publisher
Elsevier Inc
Type
journal article