2. Academic Validation
  3. A combination of PARP and CHK1 inhibitors efficiently antagonizes MYCN-driven tumors

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

  • Oncogene. 2021 Oct;40(43):6143-6152. doi: 10.1038/s41388-021-02003-0.
Stefano Di Giulio  # 1,  Valeria Colicchia  # 1 2,  Fabio Pastorino 3,  Flaminia Pedretti 1 4,  Francesca Fabretti 1,  Vittoria Nicolis di Robilant 1,  Valentina Ramponi 1 5,  Giorgia Scafetta 6,  Marta Moretti 7,  Valerio Licursi 8,  Francesca Belardinilli 1,  Giovanna Peruzzi 9,  Paola Infante 9,  Bianca Maria Goffredo 10,  Anna Coppa 7,  Gianluca Canettieri 1 11,  Armando Bartolazzi 6,  Mirco Ponzoni 3,  Giuseppe Giannini 12 13,  Marialaura Petroni 1
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy.
  • 2 Department of Biology, University Tor Vergata, 00173, Rome, Italy.
  • 3 Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
  • 4 Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
  • 5 Cellular Plasticity and Disease Group, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
  • 6 Pathology Research Laboratory, Sant'Andrea University Hospital, 00189, Rome, Italy.
  • 7 Department of Experimental Medicine, University La Sapienza, 00161, Rome, Italy.
  • 8 Department of Biology and Biotechnologies "Charles Darwin", University La Sapienza, 00185, Rome, Italy.
  • 9 Center for Life Nano- & Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), Rome, Italy.
  • 10 Metabolic Pathology Lab, Ospedale Pediatrico Bambino Gesù, 00165, Roma, Italy.
  • 11 Istituto Pasteur-Fondazione Cenci Bolognetti, 00161, Rome, Italy.
  • 12 Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. giuseppe.giannini@uniroma1.it.
  • 13 Istituto Pasteur-Fondazione Cenci Bolognetti, 00161, Rome, Italy. giuseppe.giannini@uniroma1.it.
  • # Contributed equally.
PMID: 34508175 DOI: 10.1038/s41388-021-02003-0
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.

Figures
Products
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    Product Name
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  • HY-16106
    99.89%, PARP抑制剂
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