Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors.
Anton G HenssenCasie ReedEileen JiangHeathcliff Dorado GarciaJennifer von StebutIan C MacArthurPatrick HundsdoerferJun Hyun KimElisa De StanchinaYasumichi KuwaharaHajime HosoiNeil J GanemFilemon Dela CruzAndrew L KungJohannes H SchulteJohn H J PetriniAlex KentsisPublished in: Science translational medicine (2018)
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.
Keyphrases
- dna repair
- dna damage
- induced apoptosis
- oxidative stress
- endoplasmic reticulum stress
- endothelial cells
- dna damage response
- cell cycle arrest
- diabetic rats
- induced pluripotent stem cells
- high glucose
- poor prognosis
- type diabetes
- wild type
- signaling pathway
- dna methylation
- cell death
- copy number
- binding protein
- gene expression
- drug delivery
- metabolic syndrome
- drug induced
- combination therapy
- genome wide
- pluripotent stem cells
- single molecule
- minimally invasive
- cell proliferation
- replacement therapy
- extracellular matrix
- transcription factor
- cell free
- cancer therapy
- adipose tissue
- insulin resistance
- childhood cancer