Drug screening of sarcoma cells: finding shared sensitivities

Many of the >130 WHO-defined sarcoma subtypes are chemoresistant. To identify drug candidates with potential for repurposing in sarcomas with unmet need, we screened structurally diverse small molecules across 20 sarcoma cell lines of various histologies. The screen included 1387 compounds from the Custom Clinical Collection, NCI Approved Oncology Set IV, and Selleck Bioactive Collection. The most effective agents were microtubule inhibitors, aurora kinase inhibitors, and heat shock protein inhibitors. Differential drug sensitivity was observed by sarcoma subtype. Ewing sarcoma, for example, was sensitive to aurora kinases and to TORIN-2 (an mTOR inhibitor). In contrast, myxoid liposarcoma and synovial sarcomas exhibited marked sensitivity to SNS-032, a CDK2/7/9 inhibitor identified by our screen. Interestingly, SNS-032 abrogates the downstream YAP pathway, a known driver pathway in the growth of these histotypes. Therefore, similar drug responses across histologies may indicate shared driver pathways and vulnerabilities.