| RRC ID |
52634
|
| 著者 |
Shen J, Najafi S, Stäble S, Fabian J, Koeneke E, Kolbinger FR, Wrobel JK, Meder B, Distel M, Heimburg T, Sippl W, Jung M, Peterziel H, Kranz D, Boutros M, Westermann F, Witt O, Oehme I.
|
| タイトル |
A kinome-wide RNAi screen identifies ALK as a target to sensitize neuroblastoma cells for HDAC8-inhibitor treatment.
|
| ジャーナル |
Cell Death Differ
|
| Abstract |
The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3-6 µM PCI-34051 or 10 µM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05 µM (ALK-amplified) to 0.8 µM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n = 88) and the German Neuroblastoma Trial cohort (n = 649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma.
|
| 巻・号 |
25(12)
|
| ページ |
2053-2070
|
| 公開日 |
2018-12-1
|
| DOI |
10.1038/s41418-018-0080-0
|
| PII |
10.1038/s41418-018-0080-0
|
| PMID |
29515255
|
| PMC |
PMC6261943
|
| MeSH |
Anaplastic Lymphoma Kinase / antagonists & inhibitors
Anaplastic Lymphoma Kinase / genetics*
Anaplastic Lymphoma Kinase / metabolism
Animals
Antineoplastic Agents / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Differentiation / drug effects
Cell Proliferation / drug effects
Crizotinib / pharmacology
Drug Screening Assays, Antitumor
Histone Deacetylases / genetics
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / pharmacology
Indoles / pharmacology
Neuroblastoma / drug therapy*
Neuroblastoma / metabolism
Neuroblastoma / pathology
Protein Kinase Inhibitors / pharmacology*
RNA Interference*
Repressor Proteins / antagonists & inhibitors*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Tumor Cells, Cultured
Zebrafish
|
| IF |
10.717
|
| 引用数 |
5
|
| リソース情報 |
| ヒト・動物細胞 |
NB-1(RCB1953) |
