Survey of ex vivo drug combination effects in chronic lymphocytic leukemia reveals synergistic drug effects and genetic dependencies
Open Access
- 1 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 34 (11), 2934-2950
- https://doi.org/10.1038/s41375-020-0846-5
Abstract
Drug combinations that target critical pathways are a mainstay of cancer care. To improve current approaches to combination treatment of chronic lymphocytic leukemia (CLL) and gain insights into the underlying biology, we studied the effect of 352 drug combination pairs in multiple concentrations by analysing ex vivo drug response of 52 primary CLL samples, which were characterized by "omics" profiling. Known synergistic interactions were confirmed for B-cell receptor (BCR) inhibitors with Bcl-2 inhibitors and with chemotherapeutic drugs, suggesting that this approach can identify clinically useful combinations. Moreover, we uncovered synergistic interactions between BCR inhibitors and afatinib, which we attribute to BCR activation by afatinib through BLK upstream of BTK and PI3K. Combinations of multiple inhibitors of BCR components (e.g., BTK, PI3K, SYK) had effects similar to the single agents. While PI3K and BTK inhibitors produced overall similar effects in combinations with other drugs, we uncovered a larger response heterogeneity of combinations including PI3K inhibitors, predominantly in CLL with mutated IGHV, which we attribute to the target's position within the BCR-signaling pathway. Taken together, our study shows that drug combination effects can be effectively queried in primary cancer cells, which could aid discovery, triage and clinical development of drug combinations.Keywords
Funding Information
- Deutsche Krebshilfe ((“Mildred-Scheel” professorship)
- European Molecular Biology Laboratory
- University of Heidelberg | Medizinischen Fakultät Heidelberg, Universität Heidelberg (Physician Scientist Program)
- Jose Carreras Leukämie Stiftung
- EC | Horizon 2020 Framework Programme (TRANSCAN IV (GCL-CLL))
- Krebsliga Schweiz
- Monique Dornonville de la Cour - Stiftung CRC funding program der UZH CRPP “Next Generation Drug Response Profiling for Personalized Cancer Care“
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