T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-Positive Non–Small Cell Lung Cancer
| Autor: | Naoki Takegawa, Junji Tsurutani, Masayuki Takeda, Hidetoshi Hayashi, Takeshi Yoshida, Kimio Yonesaka, Junko Tanizaki, Hisato Kawakami, Satomi Watanabe, Kazuhiko Nakagawa |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Dasatinib Apoptosis Biology Pharmacology Mice 03 medical and health sciences T790M 0302 clinical medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Animals Humans Osimertinib Viability assay Lung cancer Protein Kinase Inhibitors Protein kinase B Cell Proliferation Cancer medicine.disease Xenograft Model Antitumor Assays respiratory tract diseases ErbB Receptors 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 16:2563-2571 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | T790M mutation–selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non–small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation–positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with downregulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. Mol Cancer Ther; 16(11); 2563–71. ©2017 AACR. |
| Databáze: | OpenAIRE |
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