Reference - Detail
| RRC ID | 51765 |
|---|---|
| Author | 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. |
| Title | Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant. |
| Journal | 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. |
| Volume | 76(15) |
| Pages | 4579-91 |
| Published | 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 |
| Times Cited | 11 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 3 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | NALM-6(RCB1933) |