論文 - 詳細
| RRC ID | 54855 |
|---|---|
| 著者 | Fukuda K, Takeuchi S, Arai S, Katayama R, Nanjo S, Tanimoto A, Nishiyama A, Nakagawa T, Taniguchi H, Suzuki T, Yamada T, Nishihara H, Ninomiya H, Ishikawa Y, Baba S, Takeuchi K, Horiike A, Yanagitani N, Nishio M, Yano S. |
| タイトル | Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status. |
| ジャーナル | Cancer Res |
| Abstract |
Mutations in the ALK gene are detectable in approximately 40% of ALK-rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both ALK-mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with ALK-rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. SIGNIFICANCE: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer. |
| 巻・号 | 79(7) |
| ページ | 1658-1670 |
| 公開日 | 2019-4-1 |
| DOI | 10.1158/0008-5472.CAN-18-2052 |
| PII | 0008-5472.CAN-18-2052 |
| PMID | 30737231 |
| MeSH | Anaplastic Lymphoma Kinase / antagonists & inhibitors* Anaplastic Lymphoma Kinase / genetics* Carbazoles / pharmacology Carcinoma, Non-Small-Cell Lung / enzymology Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Crizotinib / pharmacology Drug Resistance, Neoplasm Epithelial-Mesenchymal Transition / drug effects* Histone Deacetylase Inhibitors / pharmacology Humans Hydroxamic Acids / pharmacology Lung Neoplasms / enzymology Lung Neoplasms / pathology* MicroRNAs / genetics Mutation* Piperidines / pharmacology Protein Kinase Inhibitors / pharmacology* |
| IF | 8.378 |
| 引用数 | 17 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 13 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5(RCB0211) |