MYCN drives aggressive behavior and refractoriness to chemotherapy, in several tumors. Since MYCN inactivation in clinical settings is not achievable, alternative vulnerabilities of MYCN-driven tumors need to be explored to identify more effective and less toxic therapies. We previously demonstrated that PARP inhibitors enhance MYCN-induced replication stress and promote mitotic catastrophe, counteracted by CHK1. Here, we showed that PARP and CHK1 inhibitors synergized to induce death in neuroblastoma cells and in primary cultures of SHH-dependent medulloblastoma, their combination being more effective in MYCN amplified and MYCN overexpressing cells compared to MYCN non-amplified cells. Although the MYCN amplified IMR-32 cell line carrying the p.Val2716Ala ATM mutation showed the highest sensitivity to the drug combination, this was not related to ATM status, as indicated by CRISPR/Cas9-based correction of the mutation. Suboptimal doses of the CHK1 inhibitor MK-8776 plus the PARP inhibitor olaparib led to a MYCN-dependent accumulation of DNA damage and cell death in vitro and significantly reduced the growth of four in vivo models of MYCN-driven tumors, without major toxicities. Our data highlight the combination of PARP and CHK1 inhibitors as a new potential chemo-free strategy to treat MYCN-driven tumors, which might be promptly translated into clinical trials.

A combination of PARP and CHK1 inhibitors efficiently antagonizes MYCN-driven tumors / Di Giulio, Stefano; Colicchia, Valeria; Pastorino, Fabio; Pedretti, Flaminia; Fabretti, Francesca; Nicolis di Robilant, Vittoria; Ramponi, Valentina; Scafetta, Giorgia; Moretti, Marta; Licursi, Valerio; Belardinilli, Francesca; Peruzzi, Giovanna; Infante, Paola; Goffredo, Bianca Maria; Coppa, Anna; Canettieri, Gianluca; Bartolazzi, Armando; Ponzoni, Mirco; Giannini, Giuseppe; Petroni, Marialaura. - In: ONCOGENE. - ISSN 0950-9232. - (2021). [10.1038/s41388-021-02003-0]

A combination of PARP and CHK1 inhibitors efficiently antagonizes MYCN-driven tumors

Di Giulio, Stefano
Primo
;
Colicchia, Valeria
Secondo
;
Pedretti, Flaminia;Fabretti, Francesca;Nicolis di Robilant, Vittoria;Ramponi, Valentina;Scafetta, Giorgia;Moretti, Marta;Licursi, Valerio;Belardinilli, Francesca;Peruzzi, Giovanna;Infante, Paola;Coppa, Anna;Canettieri, Gianluca;Bartolazzi, Armando;Giannini, Giuseppe
Penultimo
;
Petroni, Marialaura
Ultimo
2021

Abstract

MYCN drives aggressive behavior and refractoriness to chemotherapy, in several tumors. Since MYCN inactivation in clinical settings is not achievable, alternative vulnerabilities of MYCN-driven tumors need to be explored to identify more effective and less toxic therapies. We previously demonstrated that PARP inhibitors enhance MYCN-induced replication stress and promote mitotic catastrophe, counteracted by CHK1. Here, we showed that PARP and CHK1 inhibitors synergized to induce death in neuroblastoma cells and in primary cultures of SHH-dependent medulloblastoma, their combination being more effective in MYCN amplified and MYCN overexpressing cells compared to MYCN non-amplified cells. Although the MYCN amplified IMR-32 cell line carrying the p.Val2716Ala ATM mutation showed the highest sensitivity to the drug combination, this was not related to ATM status, as indicated by CRISPR/Cas9-based correction of the mutation. Suboptimal doses of the CHK1 inhibitor MK-8776 plus the PARP inhibitor olaparib led to a MYCN-dependent accumulation of DNA damage and cell death in vitro and significantly reduced the growth of four in vivo models of MYCN-driven tumors, without major toxicities. Our data highlight the combination of PARP and CHK1 inhibitors as a new potential chemo-free strategy to treat MYCN-driven tumors, which might be promptly translated into clinical trials.
2021
Targeted therapies; paediatric cancer; DNA damage checkpoints; MYCN
01 Pubblicazione su rivista::01a Articolo in rivista
A combination of PARP and CHK1 inhibitors efficiently antagonizes MYCN-driven tumors / Di Giulio, Stefano; Colicchia, Valeria; Pastorino, Fabio; Pedretti, Flaminia; Fabretti, Francesca; Nicolis di Robilant, Vittoria; Ramponi, Valentina; Scafetta, Giorgia; Moretti, Marta; Licursi, Valerio; Belardinilli, Francesca; Peruzzi, Giovanna; Infante, Paola; Goffredo, Bianca Maria; Coppa, Anna; Canettieri, Gianluca; Bartolazzi, Armando; Ponzoni, Mirco; Giannini, Giuseppe; Petroni, Marialaura. - In: ONCOGENE. - ISSN 0950-9232. - (2021). [10.1038/s41388-021-02003-0]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1569898
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