TY - JOUR
T1 - Acute sensitivity of Ph-like acute lymphoblastic leukemia to the SMAC-mimetic birinapant
AU - Richmond, Jennifer
AU - Robbins, Alissa
AU - Evans, Kathryn
AU - Beck, Dominik
AU - Kurmasheva, Raushan T.
AU - Billups, Catherine A.
AU - Carol, Hernan
AU - Heatley, Sue
AU - Sutton, Rosemary
AU - Marshall, Glenn M.
AU - White, Deborah
AU - Pimanda, John
AU - Houghton, Peter J.
AU - Smith, Malcolm A.
AU - Lock, Richard B.
N1 - Funding Information:
The authors thank Elvira van Straten for technical assistance and TetraLogic Pharmaceuticals Corporation for providing birinapant. Children's Cancer Institute Australia is affiliated with UNSW Australia and the Sydney Children's Hospitals Network. This research was funded by grants from the National Cancer Institute (NOI-CM-42216 and NOI-CM-91001-03). R.B. Lock is supported by a Senior Research Fellowship (1059804) from the Australian National Health and Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84982734852&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-0523
DO - 10.1158/0008-5472.CAN-16-0523
M3 - Article
C2 - 27302164
AN - SCOPUS:84982734852
SN - 0008-5472
VL - 76
SP - 4579
EP - 4591
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -