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 9.13
Human and Animal Cells NALM-6(RCB1933)