Abstract
It was recently demonstrated that the EWSR1-FLI1 t(11;22)(q24;12) translocation contributes to the hypersensitivity of Ewing sarcoma to PARP inhibitors, prompting clinical evaluation of olaparib in a cohort of heavily pretreated Ewing sarcoma tumors. Unfortunately, olaparib activity was disappointing, suggesting an underappreciated resistance mechanism to PARP inhibition in patients with Ewing sarcoma. We sought to elucidate the resistance factors to PARP inhibitor therapy in Ewing sarcoma and identify a rational drug combination capable of rescuing PARP inhibitor activity. We employed a pair of cell lines derived from the same patient with Ewing sarcoma prior to and following chemotherapy, a panel of Ewing sarcoma cell lines, and several patient-derived xenograft (PDX) and cell line xenograft models. We found olaparib sensitivity was diminished following chemotherapy. The matched cell line pair revealed increased expression of the antiapoptotic 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, whereas the addition of the BCL-2/XL inhibitor navitoclax led to tumor growth inhibition. In 2 PDXs, 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 Ewing sarcoma cells to olaparib, revealing a dual necessity for BCL-2 and BCL-XL in Ewing sarcoma survival. These data reveal BCL-2 and BCL-XL act together to drive olaparib resistance in Ewing sarcoma and reveal a novel, rational combination therapy that may be put forward for clinical trial testing.
Highlights
The Ewing family of tumors (EWFTs), consisting of primitive neuroectodermal tumor (PNET) and Ewing sarcoma, is a malignancy of predominantly bone
Resistance to olaparib was maintained in this chemotherapy-resistant model in vivo, whereas the addition of the BCL-2/XL inhibitor navitoclax led to tumor growth inhibition
In 2 patient-derived xenograft (PDX), olaparib and navitoclax were minimally effective as monotherapy, yet induced dramatic tumor growth inhibition when dosed in combination
Summary
The Ewing family of tumors (EWFTs), consisting of primitive neuroectodermal tumor (PNET) and Ewing sarcoma, is a malignancy of predominantly bone. These cancers are diagnosed most often in children and adolescents. Great strides have been made in treating localized disease by using intensive neoadjuvant and adjuvant chemotherapy regimens, increasing the 5-year survival from about 10% to approximately 75%. The EWSR1-FLI1 t(11;22)(q24;q12) translocation event is found in approximately 90% of EWFTs. Since the identification of EWSR1-FLI1 in Ewing sarcoma, it has become clear that the resultant fusion oncogene is the vital driving event in these tumors [2,3,4,5,6,7]. The molecular consequence of juxtaposing the EWSR1 and FLI1 genes is a EWS-FLI1 fusion protein where EWS potently increases the ability of transcription factor FLI1 to activate or suppress target genes
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