Chromosome 11q loss and MYCN amplification demonstrate synthetic lethality with checkpoint kinase 1 inhibition in neuroblastoma
Keller, Kaylee M.; Eleveld, Thomas F.; Schild, Linda; van den Handel, Kim; van den Boogaard, Marlinde; Amo-Addae, Vicky; Eising, Selma; Ober, Kimberley; Koopmans, Bianca; Looijenga, Leendert; Tytgat, Godelieve A.M.; Ylstra, Bauke; Molenaar, Jan J.; Dolman, M. Emmy M.; van Hooff, Sander R.
(2022) Frontiers in Oncology, volume 12, pp. 1 - 13
(Article)
Abstract
Neuroblastoma is the most common extracranial solid tumor found in children and despite intense multi-modal therapeutic approaches, low overall survival rates of high-risk patients persist. Tumors with heterozygous loss of chromosome 11q and MYCN amplification are two genetically distinct subsets of neuroblastoma that are associated with poor patient outcome. Using
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an isogenic 11q deleted model system and high-throughput drug screening, we identify checkpoint kinase 1 (CHK1) as a potential therapeutic target for 11q deleted neuroblastoma. Further investigation reveals MYCN amplification as a possible additional biomarker for CHK1 inhibition, independent of 11q loss. Overall, our study highlights the potential power of studying chromosomal aberrations to guide preclinical development of novel drug targets and combinations. Additionally, our study builds on the growing evidence that DNA damage repair and replication stress response pathways offer therapeutic vulnerabilities for the treatment of neuroblastoma.
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Keywords: checkpoint kinase 1 (CHK1), chromosome 11q deletion, MYCN amplification, neuroblastoma, pediatric cancer, prexasertib, replication stress, synergy, Oncology, Cancer Research
ISSN: 2234-943X
Publisher: Frontiers Media S.A.
Note: Funding Information: This project was financially supported by COMPASS consortium (Award No. ERAPERMED2018-121 within the ERAPerMED framework). Publisher Copyright: Copyright © 2022 Keller, Eleveld, Schild, van den Handel, van den Boogaard, Amo-Addae, Eising, Ober, Koopmans, Looijenga, Tytgat, Ylstra, Molenaar, Dolman and van Hooff.
(Peer reviewed)