MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma.
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Embargo End Date
Authors
King, D
Li, XD
Almeida, GS
Kwok, C
Gravells, P
Harrison, D
Burke, S
Hallsworth, A
Jamin, Y
George, S
Robinson, SP
Lord, CJ
Poon, E
Yeomanson, D
Chesler, L
Bryant, HE
Li, XD
Almeida, GS
Kwok, C
Gravells, P
Harrison, D
Burke, S
Hallsworth, A
Jamin, Y
George, S
Robinson, SP
Lord, CJ
Poon, E
Yeomanson, D
Chesler, L
Bryant, HE
Document Type
Journal Article
Date
2020-06-09
Date Accepted
2019-10-03
Abstract
This study investigates the influence expression of the MYCN oncogene has on the DNA damage response, replication fork progression and sensitivity to PARP inhibition in neuroblastoma. In a panel of neuroblastoma cell lines, MYCN amplification or MYCN expression resulted in increased cell death in response to a range of PARP inhibitors (niraparib, veliparib, talazoparib and olaparib) compared to the response seen in non-expressing/amplified cells. MYCN expression slowed replication fork speed and increased replication fork stalling, an effect that was amplified by PARP inhibition or PARP1 depletion. Increased DNA damage seen was specifically induced in S-phase cells. Importantly, PARP inhibition caused a significant increase in the survival of mice bearing MYCN expressing tumours in a transgenic murine model of MYCN expressing neuroblastoma. Olaparib also sensitized MYCN expressing cells to camptothecin- and temozolomide-induced cell death to a greater degree than non-expressing cells. In summary, MYCN expression leads to increased replication stress in neuroblastoma cells. This effect is exaggerated by inhibition of PARP, resulting in S-phase specific DNA damage and ultimately increased tumour cell death. PARP inhibition alone or in combination with classical chemotherapeutics is therefore a potential therapeutic strategy for neuroblastoma and may be more effective in MYCN expressing tumours.
Citation
Oncotarget, 2020, 11 (23), pp. 2141 - 2159
Source Title
Publisher
Impact Journals, LLC
ISSN
1949-2553
eISSN
1949-2553
Research Team
Gene Function
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI
Paediatric Solid Tumour Biology and Therapeutics
Pre-Clinical MRI