EXTH-71. AUTOMATED AND MULTIPLEXED COMBINATORIAL DRUG SCREENING OF FDA-APPROVED DRUGS IDENTIFIES POTENTIAL SYNERGISTIC DRUG PARTNERS FOR THE TREATMENT OF AGGRESSIVE MENINGIOMAS

Abstract

Abstract The goal of combinatorial therapy is to improve the effectiveness of treatment by targeting multiple aspects of cancer cells or by overcoming resistance to single drugs. In search of effective synergistic drug combinations for the treatment of aggressive meningiomas, we performed an automated and multiplexed combinatorial drug screening of 166 FDA-approved anticancer drugs in three grade 3 meningioma cell lines. Three anaplastic meningioma cell lines (NCH93, IOMM-Lee, and KT21-MG1) were stably transduced with blue, green, and red fluorescence proteins. The cell lines were multiplexed into 384-well plates and treated in 5x5 dose-response matrices (1 to 1000 nmol/L) for 48 hours by the automated liquid handler Hamilton MicroLAB STAR®. The drug library consisted of 166 FDA-approved anticancer drugs. To demultiplex cell viability from a single well, fluorescence as a surrogate marker for viability was measured before adding an ATP-based end-point viability assay, which served as an independent combined result of all cell lines (combined group). Synergism was calculated by the ZIP Synergy model and was defined as a ZIP score over 10. This drug screening effort generated 13695 unique drug-drug combinations per cell line. Most synergistic combinations were observed in the combined group (n = 188, 1.37%), followed by IOMM-Lee (n = 157, 1.14%), and KT21-MG1 (n = 122, 0.88%). The lowest number of synergistic combinations was observed in NCH93 (n = 75, 0.54%). Interestingly, 86 combinations were uniquely found in IOMM-Lee, 54 in KT21-MG1, and 20 in NCH93, indicating specific tumor vulnerabilities. 19 drug combinations were observed in all cell lines. Of those, the drugs Temsirolimus, Gemcitabine, and Romidepsin were highly enriched. For example, mTORi Temsirolimus concordantly showed strong synergism with the androgen receptor antagonist Darolutamide in all cell lines (ZIP score: 27.75, P< .0001). This comprehensive combinatorial drug screening identified synergistic drug-drug partners for the treatment of aggressive meningiomas. Validation studies in patient-derived meningioma organoids are ongoing.