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Sci Transl Med. 2017 Nov 1;9(414). pii: eaam9078. doi: 10.1126/scitranslmed.aam9078.

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

Author information

1
Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Berlin Institute of Health, 10178 Berlin, Germany.
3
Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
4
German Cancer Consortium (DKTK), 10117 Berlin, Germany.
5
Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
8
Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
9
Section of Hematology and Medical Oncology, Department of Pharmacology, Boston University School of Medicine, Boston, MA 02215, USA.
10
Department of Pediatrics, Weill Cornell Medical College of Cornell University and Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Deutsches Krebsforschungszentrum Heidelberg, 69120 Heidelberg, Germany.
12
Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. kentsisresearchgroup@gmail.com.

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 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 discovered that mouse and human cells deficient in nonhomologous 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 sensitivity 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 most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed 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 substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.

PMID:
29093183
PMCID:
PMC5683417
DOI:
10.1126/scitranslmed.aam9078
[Indexed for MEDLINE]
Free PMC Article

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