Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant.
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.
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
Jennifer
J
Richmond
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
Alissa
A
Robbins
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
Kathryn
K
Evans
Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
Dominik
D
Beck
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Raushan T
RT
Kurmasheva
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Catherine A
CA
Billups
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
Hernan
H
Carol
South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia.
Sue
S
Heatley
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
Rosemary
R
Sutton
Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia.
Glenn M
GM
Marshall
South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia.
Deborah
D
White
Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia.
John
J
Pimanda
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Peter J
PJ
Houghton
Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
Malcolm A
MA
Smith
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Sydney, Australia. RLock@ccia.org.au.
Richard B
RB
Lock
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D004151:Dipeptides; D007211:Indoles; C582429:birinapant