Figure 5.

Discovery of new synergistic combination therapy including Venetoclax (BCL2) and AZD5991 (MCL1). (A) Schematic overview of assay setup. GBM8, GSC11, or GSC7-10 were seeded in 384-well plates and 24 h after seeding, drug combinations were added as previously described. When 3 drugs were used, the titration of the third drug was performed over replicate plates where the 2 other drugs were titrated on. On day 4, a readout with CellTiter-Glo 3D was performed and synergy (ie, sum of synergy and antagonism) was calculated via Combenefit. (B) Schematic depiction of pathways targeted by the different drugs. Obatoclax Mesylate is a broad BCL-family targeting drug while Venetoclax is specific for BCL2 and AZD5991 is specific for MCL1. Lapatinib targets both EGFR and HER2 (ERBB2). (C) Scatterplot showing the IC50 bioactivity of Obatoclax Mesylate, Venetoclax and AZD5991 in μM concentrations. Curated data was obtained from CHEMBL as well as from Tron et al.³⁹ (D) Histogram showing the synergy scores according to Loewe additivity model (y-axis) for Lapatinib combined with Thapsigargin, Lapatinib combined with Obatoclax Mesylate, Lapatinib combined with Venetoclax, Lapatinib combined with AZD5991 and Venetoclax combined with AZD5991 on GBM8 (light red), GSC11 (red), and GSC7-10 (dark red). Data are shown as mean ± SEM.