PGBD5 expression in pediatric solid tumors confers sensitivity to inhibitors of DNA damage signaling.
Major finding: PGBD5 expression in pediatric solid tumors confers sensitivity to inhibitors of DNA damage signaling.
Concept: The ATM inhibitor AZD6738 induces accumulation of DNA damage and apoptosis to suppress tumor growth.
Impact: PGBD5+ tumors may respond to DNA damage signaling inhibitors alone or in combination with chemotherapy.
Targeted therapies are needed to treat pediatric solid tumors, but these tumors have relatively few recurrent mutations. PiggyBac transposable element derived 5 (PGBD5) promotes site-specific genomic rearrangements and is expressed in the majority of pediatric solid tumors. DNA transposase-mediated DNA rearrangements require DNA repair, primarily nonhomologous end joining (NHEJ), to restore intact target sites, prompting Henssen and colleagues to hypothesize that PGBD5-expressing cells may require DNA damage repair and signaling, creating a potentially targetable vulnerability in these cells. Consistent with this hypothesis, expression of PGBD5 induced cell death in mouse embryonic fibroblasts (MEF) with deficient NHEJ, whereas wild-type MEFs were not affected, indicating that PGBD5-expressing cells require NHEJ. Similarly, PGBD5 expression was sufficient to confer susceptibility to inhibitors of DNA damage signaling including the ATR inhibitor AZD6738 and the ATM inhibitor KU60019. Pediatric tumor cells that express PGBD5, including rhabdoid tumor, medulloblastoma, neuroblastoma, and Ewing sarcoma cells, were sensitive to AZD6738 treatment, accumulating unrepaired DNA damage and undergoing apoptosis. Depletion of PGBD5 reversed the sensitivity to AZD6738, further indicating that PGBD5 expression is required for the increased sensitivity of these tumor cells to inhibition of DNA damage repair. In vivo, AZD6738 induced DNA damage and apoptosis and suppressed tumor growth in xenograft models of high-risk neuroblastoma and medulloblastoma. In a neuroblastoma patient-derived xenograft, the antitumor efficacy of AZD6738 was enhanced by the addition of the chemotherapeutic drug cisplatin, which is often used to treat pediatric tumors. In addition to suggesting that PGBD5-expressing tumors depend on NHEJ, these findings suggest that pediatric solid tumors expressing PGBD5 may be sensitive to treatment with inhibitors of DNA damage signaling including AZD6738, and these therapies may be potentially beneficial in combination with standard chemotherapy.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.