High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells.

Abstract

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.

• Authors: Lesley A Mathews Griner, Rajarshi Guha, Paul Shinn, Ryan M Young, Jonathan M Keller, Dongbo Liu, Ian S Goldlust, Adam Yasgar, Crystal McKnight, Matthew B Boxer, Damien Y Duveau, Jian-Kang Jiang, Sam Michael, Tim Mierzwa, Wenwei Huang, Martin J Walsh, Bryan T Mott, Paresma Patel, William Leister, David J Maloney, Christopher A Leclair, Ganesha Rai, Ajit Jadhav, Brian D Peyser, Christopher P Austin, Scott E Martin, Anton Simeonov, Marc Ferrer, Louis M Staudt, Craig J Thomas
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 6 Pg. 2349-54 (Feb 11 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24469833 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Adenine

Topics

• Adenine (analogs & derivatives)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (immunology)
• Cell Line, Tumor
• High-Throughput Screening Assays
• Humans
• Lymphoma, Large B-Cell, Diffuse (immunology, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Piperidines
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)