| RRC ID |
51765
|
| 著者 |
Richmond J, Robbins A, Evans K, Beck D, Kurmasheva RT, Billups CA, Carol H, Heatley S, Sutton R, Marshall GM, White D, Pimanda J, Houghton PJ, Smith MA, Lock RB.
|
| タイトル |
Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant.
|
| ジャーナル |
Cancer Res
|
| Abstract |
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579-91. ©2016 AACR.
|
| 巻・号 |
76(15)
|
| ページ |
4579-91
|
| 公開日 |
2016-8-1
|
| DOI |
10.1158/0008-5472.CAN-16-0523
|
| PII |
0008-5472.CAN-16-0523
|
| PMID |
27302164
|
| PMC |
PMC4970887
|
| MeSH |
Animals
Apoptosis
Cell Line, Tumor
Dipeptides / administration & dosage
Dipeptides / pharmacology
Dipeptides / therapeutic use*
Female
Gene Expression
Humans
Indoles / administration & dosage
Indoles / pharmacology
Indoles / therapeutic use*
Mice
Mice, Inbred NOD
Mice, SCID
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
|
| IF |
9.727
|
| 引用数 |
11
|
| リソース情報 |
| ヒト・動物細胞 |
NALM-6(RCB1933) |
