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High-throughput Identification of Synergistic Drug Combinations by the Overlap2 Method
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Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma

K Tomska1, R Kurilov2,3, K S Lee4

  • 1Molecular Therapy in Haematology and Oncology & Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany. katarzyna.tomska@med.uni-heidelberg.de.

Scientific Reports
|August 15, 2018
PubMed

Insights

This study profiles drug responses in Burkitt lymphoma (BL) cell lines, identifying sensitivities and synergistic drug combinations. Targeting CDK and BET pathways shows promise as a novel therapeutic strategy for BL.

Area of Science:

  • Hematology
  • Oncology
  • Pharmacology

Background:

  • Burkitt lymphoma (BL) is an aggressive B-cell malignancy characterized by MYC translocation.
  • Understanding drug sensitivities and combinations is crucial for developing effective BL treatments.

Purpose of the Study:

  • To profile drug responses in a comprehensive set of Burkitt lymphoma cell lines.
  • To systematically investigate synergistic drug combinations for potential BL therapies.

Main Methods:

  • Drug response profiling of 42 blood cancer cell lines (17 BL) against 32 targeted drugs.
  • Systematic screening of drug combinations, including BET, BTK, and PI3K inhibitors.

Main Results:

  • Identified cell line-specific sensitivities, including to venetoclax (BCL2 overexpression) and kinase inhibitors.
  • Discovered synergistic combinations of PI3K/BTK inhibitors with Akt, mTOR, BET, and doxorubicin inhibitors.
  • BET inhibitor OTX015 demonstrated synergy in 41% of combinations, particularly with PI3K/AKT/mTOR inhibitors. Strongest synergy observed with CDK 2/7/9 inhibitor SNS032 and OTX015.

Conclusions:

  • Drug combination profiling provides a landscape of therapeutic vulnerabilities in BL.
  • Targeting CDK and BET pathways represents a novel and promising therapeutic strategy for Burkitt lymphoma.

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