The Ewing family of tumors rely on BCL-2 and BCL-XL to escape PARP inhibitor toxicity

Purpose: It was recently demonstrated that EWS-FLI1 contributes to the hypersensitivity of Ewing Sarcoma (ES) to PARP inhibitors, prompting clinical evaluation of olaparib in a cohort of heavily pre-treated ES patients. Unfortunately, olaparib activity was disappointing, suggesting an underappreciated resistance mechanism to PARP inhibition in ES patients. We sought to elucidate the resistance factors to PARP inhibitor therapy in ES and identify a rational drug combination capable of rescuing PARP inhibitor activity. Experimental Design: By employing a pair of cell lines derived from the same ES patient prior to and following chemotherapy, a panel of ES cell lines, and several PDX and xenograft models. Results: We found olaparib sensitivity was diminished following chemoresistance. The matched cell line pair revealed increased expression of the anti-apoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. Resistance to olaparib was maintained in this chemotherapy-resistant model in vivo, while the addition of the BCL-2/X_L inhibitor navitoclax led to complete tumor growth inhibition. In two patient-derived xenografts, olaparib and navitoclax were minimally effective as monotherapy, yet induced dramatic tumor growth inhibition when dosed in combination. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone by venetoclax is insufficient to sensitize ES cells to olaparib, revealing a dual necessity for BCL-2 and BCL-X_L in ES survival. Conclusion: These data reveal BCL-2 and BCL-X_L act together to drive olaparib resistance in ES and reveals a novel, rational combination therapy that may be put forward for clinical trial testing.

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