論文 - 詳細
| RRC ID | 43816 |
|---|---|
| 著者 | Yamada T, Takeuchi S, Nakade J, Kita K, Nakagawa T, Nanjo S, Nakamura T, Matsumoto K, Soda M, Mano H, Uenaka T, Yano S. |
| タイトル | Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. Although crizotinib, a dual tyrosine kinase inhibitor (TKI) of ALK and Met, shows dramatic effect against EML4-ALK lung cancer cells, these cells can acquire resistance to crizotinib by several mechanisms, including ALK amplification and gatekeeper mutation. We determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells. EXPERIMENTAL DESIGN:We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo. RESULTS:EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGF receptor (EGFR) ligands, such as EGF, TGF-α, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. Hepatocyte growth factor (HGF) activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs resensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively. CONCLUSIONS:Paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, suggesting that receptor ligands from microenvironment may be additional targets during treatment with ALK inhibitors. |
| 巻・号 | 18(13) |
| ページ | 3592-602 |
| 公開日 | 2012-7-1 |
| DOI | 10.1158/1078-0432.CCR-11-2972 |
| PII | 1078-0432.CCR-11-2972 |
| PMID | 22553343 |
| MeSH | Adaptor Proteins, Signal Transducing / metabolism Anaplastic Lymphoma Kinase Animals Antineoplastic Agents / pharmacology Cell Line, Tumor Cell Proliferation / drug effects Coculture Techniques Crizotinib Drug Resistance, Neoplasm* Endothelial Cells / metabolism ErbB Receptors / antagonists & inhibitors ErbB Receptors / metabolism Erlotinib Hydrochloride Fibroblasts / metabolism Gene Amplification Hepatocyte Growth Factor / antagonists & inhibitors Hepatocyte Growth Factor / metabolism Hepatocyte Growth Factor / physiology Humans Intercellular Signaling Peptides and Proteins / pharmacology Intercellular Signaling Peptides and Proteins / physiology Lung Neoplasms Male Mice Mice, SCID Mutation, Missense Oncogene Proteins, Fusion / metabolism* Paracrine Communication* Proto-Oncogene Proteins c-met / antagonists & inhibitors Proto-Oncogene Proteins c-met / metabolism Pyrazoles / pharmacology Pyridines / pharmacology Pyrimidines / pharmacology Quinazolines / pharmacology Receptor Protein-Tyrosine Kinases / antagonists & inhibitors* Receptor Protein-Tyrosine Kinases / genetics Tumor Microenvironment* Xenograft Model Antitumor Assays |
| IF | 10.107 |
| 引用数 | 68 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | MRC-5 |