Exon 16–Skipping HER2 as a Novel Mechanism of Osimertinib Resistance in EGFR L858R/T790M–Positive Non–Small Cell Lung Cancer
| Autor: | Chia Chi Hsu, Daniel Stetson, Wei-Yu Liao, Kenneth S. Thress, James Chih-Hsin Yang, Aleksandra Markovets, Bin-Chi Liao |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Lung Neoplasms Afatinib Receptor tyrosine kinase 03 medical and health sciences T790M 0302 clinical medicine Carcinoma Non-Small-Cell Lung medicine Humans Osimertinib Lung cancer Protein Kinase Inhibitors Acrylamides Aniline Compounds biology Cell growth business.industry Exons medicine.disease EGFR Tyrosine Kinase Inhibitor Therapy ErbB Receptors Editorial Commentary 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation biology.protein Cancer research business Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Transl Lung Cancer Res |
| ISSN: | 1556-0864 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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