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

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.

ATR Inhibition Potentiates PARP Inhibitor Cytotoxicity in High Risk Neuroblastoma Cell Lines by Multiple Mechanisms

“…In models of Ras-or MYC-driven cancer, signalling through these oncogenes has been shown to lead to sensitivity to ATR inhibition [54][55][56]. In NB cell lines, high MYCN expression has been shown to increase RS [32,57]. Here we have shown that amplification and overexpression of the MYCN oncogene in NB cell lines is associated with sensitivity to VE-821, confirming that MYCN driven NB cells are vulnerable to ATR inhibition.…”

A Comprehensive Analysis of Alterations in DNA Damage Repair Pathways Reveals a Potential Way to Enhance the Radio-Sensitivity of Esophageal Squamous Cell Cancer

“…Therefore, targeting DSB repair pathways is a potential effective strategy to enhance radio-sensitivity ( 4 – 6 , 8 , 11 ). As one of the most famous examples of HR inhibitors, mirin was developed against endonuclease activity of MRE11 and used to effectively inhibit multiple cancers ( 32 , 56 , 57 ). Similarly, NU7441, a highly selective inhibitor for DNA-PK, blocked NHEJ of radiation-induced DSBs and enhanced cancer radio-sensitivity ( 33 , 34 , 58 , 59 ).…”

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

“…Around 50% of HR-NB have an amplification of the MYCN oncogene, which drives proliferation and causes replication stress (117). MYCN also transcriptionally upregulates many proteins involved in DNA DSB repair, including components of the MRE11-RAD50-NBLS1 (MRN) complex (118,119), alternative NHEJ (alt-NHEJ) (120), and Bloom syndrome (BLM) helicase (121), and the cell cycle checkpoint protein CHK1 (117,122). Upregulation of these genes likely provide MYCNdriven tumors the ability to tolerate higher levels of DNA damage and replication stress.…”