Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study

Autor:	Masaya Nishino, Kenichi Suda, Junichi Soh, Akira Hamada, Toshio Fujino, Avanish Vellanki, Tetsuya Mitsudomi, Shuta Ohara, Takamasa Koga, Robert C. Doebele, Vijaya G. Tirunagaru
Rok vydání:	2021
Předmět:	Mutation business.industry Mutant non-small cell lung cancer (NSCLC) Mutagenesis (molecular biology technique) Prodrug medicine.disease medicine.disease_cause Molecular biology In vitro Oncology Cell culture medicine skin and connective tissue diseases Lung cancer business neoplasms
Zdroj:	Translational Lung Cancer Research. 10:3659-3670
ISSN:	2226-4477 2218-6751
DOI:	10.21037/tlcr-21-216
Popis:	Background HER2 (ERBB2) activating mutations are present in 2-3% of lung adenocarcinomas; however, no targeted therapy is approved for HER2-altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the in vitro activity of tarloxotinib-E in HER2-mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells. Methods Growth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six HER2 mutations or wild-type (WT) HER2, in addition to H1781 cells with HER2 exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated HER2-mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E. Results Tarloxotinib-E showed potent activity against HER2-mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC50) of tarloxotinib (inactive form) for WT HER2 was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of HER2 by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased HER3 expression was the molecular mechanism of tarloxotinib-E resistance. Conclusions Tarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::76839986160a3db63314c254fef11d0f https://doi.org/10.21037/tlcr-21-216 Zobrazit plný text záznamu