MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors

Marialaura Petroni, Francesca Sardina, Paola Infante, Armando Bartolazzi, Erica Locatelli, Francesca Fabretti, Stefano Di Giulio, Carlo Capalbo, Beatrice Cardinali, Anna Coppa, Alessandra Tessitore, Valeria Colicchia, Maria Sahùn Roncero, Francesca Belardinilli, Lucia Di Marcotullio, Silvia Soddu, Mauro Comes Franchini, Elena Petricci, Alberto Gulino, Giuseppe Giannini

Research output: Contribution to journalArticle

Abstract

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors.

Original languageEnglish
Article number895
JournalCell Death and Disease
Volume9
Issue number9
DOIs
Publication statusPublished - Sep 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Petroni, M., Sardina, F., Infante, P., Bartolazzi, A., Locatelli, E., Fabretti, F., Di Giulio, S., Capalbo, C., Cardinali, B., Coppa, A., Tessitore, A., Colicchia, V., Sahùn Roncero, M., Belardinilli, F., Di Marcotullio, L., Soddu, S., Comes Franchini, M., Petricci, E., Gulino, A., & Giannini, G. (2018). MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors. Cell Death and Disease, 9(9), [895]. https://doi.org/10.1038/s41419-018-0924-z