The DNA transposase, piggyBac transposable element-derived 5 (PGBD5), is expressed in the majority of childhood solid tumours, where it promotes site-specific genomic rearrangements. Henssen et al. hypothesized that PGBD5-expressing cells may depend on active DNA damage repair and signalling for survival. Indeed, cell lines deficient in non-homologous end-joining DNA repair died upon induction of PGBD5 expression. A panel of 19 childhood tumour cell lines was highly sensitive to the DNA damage signalling inhibitor AZD6738, which targets ATR. Oral treatment of mouse tumour models with AZD6738, including patient-derived primary neuroblastoma xenografts, significantly impaired tumour growth without toxicity.
References
Henssen, A. et al. Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Sci. Transl Med. 9, eaam9078 (2017)
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Crunkhorn, S. Inhibiting DNA damage signalling. Nat Rev Drug Discov 17, 18 (2018). https://doi.org/10.1038/nrd.2017.261
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DOI: https://doi.org/10.1038/nrd.2017.261
