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Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Item Type:Preprint
Title:Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors
Creators Name:Henssen, A.G. and Reed, Casie and Jiang, Eileen and Garcia, H.D. and von Stebut, J. and MacArthur, I.C. and Hundsdoerfer, P. and Kim, J.H. and de Stanchina, E. and Kuwahara, Y. and Hosoi, H. and Ganem, N. and Cruz, F.D. and Kung, A.L. and Schulte, J.H. and Petrini, J.H. and Kentsis, A.
Abstract:Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have now found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5 that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we found that mouse and human cells deficient in non-homologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce hypersensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment, and underwent apoptosis in both dividing and G1 phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including significant anti-tumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.
Keywords:PGBD5, AZD6738, ATR, ATM, Neuroblastoma, Medulloblastoma, Ewing Sarcoma, Rhabdoid Tumors, DNA Repair, Targeted Therapy
Publisher:Cold Spring Harbor Laboratory Press
Article Number:181040
Date:25 August 2017
Official Publication:https://doi.org/10.1101/181040
Related to:
https://edoc.mdc-berlin.de/18379/Final version

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