論文 - 詳細
| RRC ID | 72244 |
|---|---|
| 著者 | Cai J, Jacob S, Kurupi R, Dalton KM, Coon C, Greninger P, Egan RK, Stein GT, Murchie E, McClanaghan J, Adachi Y, Hirade K, Dozmorov M, Glod J, Boikos SA, Ebi H, Hao H, Caponigro G, Benes CH, Faber AC. |
| タイトル | High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition. |
| ジャーナル | Cell Rep |
| Abstract |
Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB. |
| 巻・号 | 40(4) |
| ページ | 111095 |
| 公開日 | 2022-7-26 |
| DOI | 10.1016/j.celrep.2022.111095 |
| PII | S2211-1247(22)00897-X |
| PMID | 35905710 |
| MeSH | Animals Cell Line, Tumor Mice Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Neoplasm Recurrence, Local Neuroblastoma* / drug therapy Neuroblastoma* / genetics Neuroblastoma* / pathology Neurofibromin 1* / genetics Neurofibromin 1* / metabolism Protein Kinase Inhibitors / pharmacology Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism* |
| IF | 8.109 |
| 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 | 32 |
| 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 | HCE-T(RCB2280) |