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
リソース情報
ヒト・動物細胞 HCE-T(RCB2280)