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

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.

Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor

“…Importantly, supervised analysis of distinct tumor specimens revealed potentially new tumor markers, such as PGBD5 (Supplemental Figure 1B), which we recently validated as an oncogenic DNA transposase and therapeutic target in rhabdoid tumors (14)(15)(16)(17). In the case of favorable-histology Wilms' tumor, we identified the most abundant proteins specifically detected in Wilms' tumor as compared with other non-Wilms' tumor kidney tumor urine specimens (Supplemental Figures 1, B-E).…”

“…First, reported urine proteome profiles of diverse kidney tumors provide a valuable source of potential tumor biomarkers and therapeutic targets. Our recent study of PGBD5, identified in the proteomic profiles of renal rhabdoid tumors, revealed an unanticipated mechanism of human tumor pathogenesis and molecular target for improved therapy (15)(16)(17).…”

Tea Polyphenols Attenuate Methamphetamine-Induced Neuronal Damage in PC12 Cells by Alleviating Oxidative Stress and Promoting DNA Repair

“…Unless an effective repair mechanism corrects the damage to the double helix, DNA damage may cause persistent abnormalities after mitosis and in irreplaceable cells such as neurons (Milanese et al, 2018). Fortunately, cells have evolved DNA damage repair (DDR) mechanisms to alleviate a variety of damages (Henssen et al, 2017). Once DNA damage is triggered by exogenous and endogenous factors such as free radicals, the DDR can be activated to alter expressions of the damage sensor γ-H2AX and subsequent signal transduction pathways such as ATM/Chk2 pathway-related proteins (Ronco et al, 2017;He et al, 2018).…”

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

“…DDR DNA damage response, PARP poly(ADP-ribose) polymerase, PARG poly(ADP-ribose) glycohydrolase have identified the mechanism of ATR inhibitor resistance in vitro. Henssen et al [159] recently reported that endogenous PGBD5 depletion is associated with AZD6738 resistance in human tumor cells. AZD6738 causes unrepaired DNA damage to be accumulated in PGBD5-expressing cells, resulting in G1-phase and dividing cell apoptosis.…”