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| Item Type: | Preprint |
|---|---|
| Title: | Exploiting a PAX3-FOXO1-induced synthetic lethal ATR dependency for rhabdomyosarcoma therapy |
| Creators Name: | García, H.D., Bei, Y., von Stebut, J., Ibáñez, G., Imami, K., Gürgen, D., Rolff, J., Helmsauer, K., Timme, N., Bardinet, V., Chamorro González, R., MacArthur, I.C., Pusch, F.F., Chen, C.Y., Schulz, J., Wengner, A.M., Furth, C., Lala, B., Eggert, A., Seifert, G., Hundsoerfer, P., Kirchner, M., Mertins, P., Selbach, M., Lissat, A., Schulte, J.H., Haase, K., Scheer, M., Ortiz, M.V. and Henssen, A.G. |
| Abstract: | Pathognomonic PAX3-FOXO1 fusion oncogene expression is associated with poor outcome in rhabdomyosarcoma. Combining genome-wide CRISPR screening with cell-based functional genetic approaches, we here provide evidence that PAX3-FOXO1 induces replication stress, resulting in a synthetic lethal dependency to ATR-mediated DNA damage-response signaling in rhabdomyosarcoma. Expression of PAX3-FOXO1 in muscle progenitor cells was not only sufficient to induce hypersensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibited increased sensitivity to structurally diverse inhibitors of ATR, a dependency that could be validated genetically. Mechanistically, ATR inhibition led to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increased sensitivity of rhabdomyosarcoma cells to PARP inhibition in vitro, and combined ATR and PARP inhibition induced regression of primary patient-derived alveolar rhabdomyosarcoma xenografts in vivo. Moreover, a genome-wide CRISPR activation screen (CRISPRa) identified FOS gene family members as inducers of resistance against ATR inhibitors. Mechanistically, FOS gene family members reduced replication stress in rhabdomyosarcoma cells. Lastly, compassionate use of ATR inhibitors in two pediatric patients suffering from relapsed PAX3-FOXO1-expressing alveolar rhabdomyosarcoma showed signs of tolerability, paving the way to clinically exploit this novel synthetic lethal dependency in rhabdomyosarcoma. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2020.12.04.411413 |
| Date: | 2020 |
| Official Publication: | https://doi.org/10.1101/2020.12.04.411413 |
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