The Ewing Family of Tumors Relies on BCL-2 and BCL-X L to Escape PARP Inhibitor Toxicity.
Autor: | Heisey DAR; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Lochmann TL; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Floros KV; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Coon CM; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Powell KM; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Jacob S; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Calbert ML; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Ghotra MS; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia., Stein GT; Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts., Maves YK; Crown Bioscience Inc., San Diego, California., Smith SC; Division of Anatomic Pathology, Virginia Commonwealth University, Richmond, Virginia., Benes CH; Massachusetts General Hospital Cancer Center, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts., Leverson JD; AbbVie, North Chicago, Illinois., Souers AJ; AbbVie, North Chicago, Illinois., Boikos SA; Hematology, Oncology and Palliative Care, School of Medicine and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia., Faber AC; VCU Philips Institute, School of Dentistry and Massey Cancer Center; Richmond, Virginia. acfaber@vcu.edu. |
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Jazyk: | angličtina |
Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Mar 01; Vol. 25 (5), pp. 1664-1675. Date of Electronic Publication: 2018 Oct 22. |
DOI: | 10.1158/1078-0432.CCR-18-0277 |
Abstrakt: | Purpose: 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. Experimental Design: 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. Results: 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/X Conclusions: These data reveal BCL-2 and BCL-X (©2018 American Association for Cancer Research.) |
Databáze: | MEDLINE |
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