AUTHOR=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. TITLE=Chromosome 11q loss and MYCN amplification demonstrate synthetic lethality with checkpoint kinase 1 inhibition in neuroblastoma JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.929123 DOI=10.3389/fonc.2022.929123 ISSN=2234-943X 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 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.