Figure 1. Combined MRX-2843 and vincristine synergize to inhibit T-ALL cell growth in high-throughput combination drug screens.

a) Illustration of a ratiometric drug screen combining the dual MERTK/FLT3 inhibitor, MRX-2843, with methotrexate and/or vincristine in a panel of 13 B- and T-ALL cell lines as measured by luminescent viability assay (72 h, Z’≥0.5). b) Single-agent dose response curves and (c) lineage-specific frequencies of combined drug synergy, additivity, or antagonism for 537 unique pairwise or triplet drug combinations as measured in parallel and assessed via the Bliss Independence model. d) Scatter plots of mean drug synergy as a function of mean growth inhibition grouped by cell lineage. Ratiometric drug synergy is conserved across T- and ETP-ALL cell lines with synergy among distinct molar ratios of MRX-2843 and vincristine. e) Drug synergy and antagonism appear at distinct doses and molar ratios in cells from the T- and ETP-ALL lineage. (c-e) Synergy represents percent reduction in cell density greater or lesser than that predicted by the Bliss Independence model with synergy (>1%) and antagonism (<−1%). (e) Sphere size and saturation correspond to the mean magnitude of synergy observed across T- and ETP-ALL cell lines (n=6) for each pairwise and triplet drug combination among 537 tested.