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

Cell Death & Disease
M PetroniG Giannini

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 accumulati...Continue Reading

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Citations

Feb 27, 2019·Current Drug Targets·Yucui Zhao, Siyu Chen
Jan 26, 2020·Scientific Reports·Takeshi Honda, Makoto Inui
Apr 21, 2020·Frontiers in Oncology·Harriet E D SouthgateDeborah A Tweddle
Sep 17, 2020·International Journal of Molecular Sciences·Samuele LodovichiAlvaro Galli
Jan 28, 2021·Cancers·Danielle P JohnsonSrividya Bhaskara
Nov 19, 2020·Trends in Cancer·Katherine E Baillie, Peter C Stirling
Jul 30, 2021·DNA Repair·Ujjayinee Ray, Sathees C Raghavan
Sep 12, 2021·Oncogene·Stefano Di GiulioMarialaura Petroni

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Methods Mentioned

BETA
transfection
PCR
xenografts
xenograft
reverse transcription-PCR

Software Mentioned

R2
GraphPRISM6
Genomics and visualization
Scan
modus
Genomics

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