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 way to explore hundreds or 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 the chemotherapy that is the standard of care for DLBCL.

 

Viability of lymphoma cells treated with ibrutinib plus Bcl-2 family inhibitors. The combination responses for ibrutinib and navitoclax as judged by (A) 6×6 matrix block evaluation of ibrutinib plus navitoclax in TMD8 cells, (B) MTS assay in 96-well plates of ibrutinib plus navitoclax in the indicated lines and (C) MTS assay in 96-well plates of ibrutinib plus ABT-199 in the indicated lines.

Viability of lymphoma cells treated with ibrutinib plus Bcl-2 family inhibitors. The combination responses for ibrutinib and navitoclax as judged by (A) 6×6 matrix block evaluation of ibrutinib plus navitoclax in TMD8 cells, (B) MTS assay in 96-well plates of ibrutinib plus navitoclax in the indicated lines and (C) MTS assay in 96-well plates of ibrutinib plus ABT-199 in the indicated lines. (Reprinted with permission Mathews Griner LA, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci USA. 2014;111(6): 2349-54. Copyright Proc Natl Acad Sci U S A. 2014.)

Publications

Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, Goldlust IS, Yasgar A, McKnight C, Boxer MB, Duveau DY, Jiang JK, Michael S, Mierzwa T, Huang W, Walsh MJ, Mott BT, Patel P, Leister W, Maloney DJ, Leclair CA, Rai G, Jadhav A, Peyser BD, Austin CP, Martin SE, Simeonov A, Ferrer M, Staudt LM, Thomas CJ. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cellsProc Natl Acad Sci USA. 2014;111(6): 2349-54.

Public Health Impact

A common strategy for killing cancer cells is to target a protein that is critical for their survival and growth. Often, targeting one protein is not effective at killing cancer cells, as they can find alternative methods to survive. This study found that using ibrutinib in combination with many other cancer drugs works better to kill cancer cells than each testeddrug by itself. This knowledge can be used to set up studies to test treating cancer patients with a combination of ibrutinib and other drugs.