論文 - 詳細
| RRC ID | 17609 |
|---|---|
| 著者 | Bachleitner-Hofmann T, Sun MY, Chen CT, Liska D, Zeng Z, Viale A, Olshen AB, Mittlboeck M, Christensen JG, Rosen N, Solit DB, Weiser MR. |
| タイトル | Antitumor activity of SNX-2112, a synthetic heat shock protein-90 inhibitor, in MET-amplified tumor cells with or without resistance to selective MET Inhibition. |
| ジャーナル | Clin Cancer Res |
| Abstract |
PURPOSE:Heat shock protein-90 (HSP-90), a molecular chaperone required by numerous oncogenic kinases [e.g., HER-2, epidermal growth factor receptor (EGFR), Raf-1, v-Src, and AKT] for conformational stability, has attracted wide interest as a novel target for cancer therapy. HSP-90 inhibition induces degradation of HSP-90 client proteins, leading to a combinatorial inhibition of multiple oncogenic signaling pathways with consecutive growth arrest and apoptosis. MET, a tyrosine kinase that is constitutively active in tumor cells with MET oncogene amplification, has recently been identified as another HSP-90 client. EXPERIMENTAL DESIGN:The aim of our study was to assess the efficacy of SNX-2112, a synthetic HSP-90 inhibitor, in 3 different MET-amplified tumor cell lines (GTL-16, MKN-45, and EBC-1) as well as PR-GTL-16 cells, a GTL-16 subline selected for resistance to the highly selective MET kinase inhibitor PHA-665752. RESULTS:In all cell lines, SNX-2112 led to degradation of MET, HER-2, EGFR, and AKT, as well as abrogation of Ras/Raf/MEK/MAPK and PI3K/AKT signaling, followed by complete cell cycle arrest. SNX-5542, an orally bioavailable prodrug of SNX-2112, displayed significant antitumor efficacy in vivo in nude mice bearing MET-amplified tumor xenografts. Importantly, HSP-90 inhibition maintained its antitumor efficacy in PR-GTL-16 cells both in vitro and in vivo, suggesting that HSP-90 inhibition could be a particularly valuable strategy in MET-amplified tumors that have acquired resistance to MET kinase inhibition. CONCLUSIONS:Our study provides evidence for the efficacy of HSP-90 inhibition in MET-amplified cancer cells, particularly when MET kinase inhibitor resistance has emerged. |
| 巻・号 | 17(1) |
| ページ | 122-33 |
| 公開日 | 2011-1-1 |
| DOI | 10.1158/1078-0432.CCR-10-0253 |
| PII | 17/1/122 |
| PMID | 21208906 |
| PMC | PMC3263825 |
| MeSH | Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects Drug Resistance, Neoplasm Drug Screening Assays, Antitumor HSP90 Heat-Shock Proteins / antagonists & inhibitors* Heterocyclic Compounds, 4 or More Rings / pharmacology* Humans Indoles / pharmacology Mice Mice, Inbred BALB C Mice, Nude Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-met / antagonists & inhibitors* Proto-Oncogene Proteins c-met / metabolism Structure-Activity Relationship Sulfones / pharmacology |
| IF | 10.107 |
| 引用数 | 29 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | MKN45(RCB1001) |