Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia.
Purpose:Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease.Experimental Design:We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity.Results:We first determined that bothNOTCH1-mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were testedin vivoand prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice.Conclusions:We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation.Clin Cancer Res; 23(4); 1012-24. ©2016 AACRSee related commentary by Carroll et al., p. 873.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Yana
Y
Pikman
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.|Bioinformatics Graduate Program, Boston University, Boston, Massachusetts.
Gabriela
G
Alexe
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Giovanni
G
Roti
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Amy Saur
AS
Conway
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Andrew
A
Furman
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Emily S
ES
Lee
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Andrew E
AE
Place
Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts.
Sunkyu
S
Kim
Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts.
Chitra
C
Saran
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Rebecca
R
Modiste
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
David M
DM
Weinstock
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
Marian
M
Harris
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Andrew L
AL
Kung
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
Lewis B
LB
Silverman
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kimberly_stegmaier@dfci.harvard.edu.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.|Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
Kimberly
K
Stegmaier
D000631:Aminopyridines / Q000008:administration & dosage*; D000818:Animals; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011687:Purines / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D011687:Purines; D003907:Dexamethasone; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C000589651:ribociclib