Targeting
| Autor: | Han, Han, Shuai, Li, Ting, Chen, Michael, Fitzgerald, Shengwu, Liu, Chengwei, Peng, Kwan Ho, Tang, Shougen, Cao, Johara, Chouitar, Jiansheng, Wu, David, Peng, Jiehui, Deng, Zhendong, Gao, Theresa E, Baker, Fei, Li, Hua, Zhang, Yuanwang, Pan, Hailin, Ding, Hai, Hu, Val, Pyon, Cassandra, Thakurdin, Eleni, Papadopoulos, Sittinon, Tang, Francois, Gonzalvez, Haiquan, Chen, Victor M, Rivera, Rachael, Brake, Sylvie, Vincent, Kwok-Kin, Wong |
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| Rok vydání: | 2021 |
| Předmět: |
Lung Neoplasms
Receptor ErbB-2 Adenocarcinoma of Lung Apoptosis Exons Mice SCID Ado-Trastuzumab Emtansine Xenograft Model Antitumor Assays Article Gene Expression Regulation Neoplastic Mice INDEL Mutation Mice Inbred NOD Antibodies Bispecific Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured Animals Humans Female skin and connective tissue diseases Cell Proliferation |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 |
| Popis: | No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC(50) of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC(50) / WT EGFR IC(50) ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20(YVMA) allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20(G776>VC) lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20(YVMA) tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20(YVMA) tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4(+) T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20(YVMA) insertion-mutant lung adenocarcinoma patients. |
| Databáze: | OpenAIRE |
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