Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.

Autor:	George SL; Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom; Children and Young People's Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT United Kingdom. Electronic address: Sally.George@icr.ac.uk., Lorenzi F; Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom., King D; Academic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom., Hartlieb S; Neuroblastoma Genomics, Hopp Children`s Cancer Center Heidelberg (KiTZ) & German Cancer Research Center (DKFZ), Heidelberg, Germany., Campbell J; Bioinformatics Core Facility, The Institute of Cancer Research, London, United Kingdom., Pemberton H; CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research London, SW3 6JB, United Kingdom., Toprak UH; Neuroblastoma Genomics, Hopp Children`s Cancer Center Heidelberg (KiTZ) & German Cancer Research Center (DKFZ), Heidelberg, Germany., Barker K; Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom., Tall J; Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom., da Costa BM; Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom., van den Boogaard ML; Princess Maxima Center for Pediatric Cancer, Utrecht, The Netherlands., Dolman MEM; Princess Maxima Center for Pediatric Cancer, Utrecht, The Netherlands., Molenaar JJ; Princess Maxima Center for Pediatric Cancer, Utrecht, The Netherlands., Bryant HE; Academic Unit of Molecular Oncology, Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom., Westermann F; Neuroblastoma Genomics, Hopp Children`s Cancer Center Heidelberg (KiTZ) & German Cancer Research Center (DKFZ), Heidelberg, Germany., Lord CJ; CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research London, SW3 6JB, United Kingdom., Chesler L; Paediatric Tumour Biology, Division of Clinical Studies, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom; Children and Young People's Unit, Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT United Kingdom.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2020 Sep; Vol. 59, pp. 102971. Date of Electronic Publication: 2020 Aug 23.
DOI:	10.1016/j.ebiom.2020.102971
Abstrakt:	Background: In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research. Methods: To evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX. We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF. Findings: In isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selective sensitivity in ATRX mutant cells to multiple PARP inhibitors and the ATM inhibitor KU60019. ATRX mutant cells also showed selective sensitivity to the DNA damaging agents, sapacitabine and irinotecan. HRR deficiency was also seen in the ATRX deleted CHLA-90 cell line, and significant sensitivity demonstrated to olaparib/irinotecan combination therapy in all ATRX LoF models. In-vivo sensitivity to olaparib/irinotecan was seen in ATRX mutant but not wild-type xenografts. Finally, sustained responses to olaparib/irinotecan therapy were seen in an ATRX deleted neuroblastoma patient derived xenograft. Interpretation: ATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic. Funding: This work was supported by Christopher's Smile, Neuroblastoma UK, Cancer Research UK, and the Royal Marsden Hospital NIHR BRC. Competing Interests: Declaration of Competing Interest Dr. Lord reports grants, personal fees and non-financial support from AstraZeneca, Merck KGaA, Artios and Vertex. Dr. Lord is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from the development as part of the ICR “Rewards to Inventors” scheme. Dr Lord has received consultancy, SAB membership or honoraria payments from: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios and has stock in Tango, Ovibio. This is outside the scope of the submitted work. Dr. Chesler reports grants from Christopher Smile Foundation, NIHR BRC, CRUK and the Neuroblastoma Society during the conduct of the study. All other authors declare no competing interests. (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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