High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells.
The clinical development of drug combinations is typically achieved through trial-and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small-molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug-drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton's tyrosine kinase inhibitor ibrutinib, which targets the chronic active B-cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT-mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL.
Division of Preclinical Innovation, National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Metabolism Branch, Center for Cancer Research, and Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Lesley A
LA
Mathews Griner
Rajarshi
R
Guha
Paul
P
Shinn
Ryan M
RM
Young
Jonathan M
JM
Keller
Dongbo
D
Liu
Ian S
IS
Goldlust
Adam
A
Yasgar
Crystal
C
McKnight
Matthew B
MB
Boxer
Damien Y
DY
Duveau
Jian-Kang
JK
Jiang
Sam
S
Michael
Tim
T
Mierzwa
Wenwei
W
Huang
Martin J
MJ
Walsh
Bryan T
BT
Mott
Paresma
P
Patel
William
W
Leister
David J
DJ
Maloney
Christopher A
CA
Leclair
Ganesha
G
Rai
Ajit
A
Jadhav
Brian D
BD
Peyser
Christopher P
CP
Austin
Scott E
SE
Martin
Anton
A
Simeonov
Marc
M
Ferrer
Louis M
LM
Staudt
Craig J
CJ
Thomas
D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D057166:High-Throughput Screening Assays; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D000225:Adenine; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib
Imbruvica; PCI-32765; translational research