Chromosome 11q loss and MYCN amplification demonstrate synthetic lethality with checkpoint kinase 1 inhibition in neuroblastoma

• DOI: 10.3389/fonc.2022.929123
• Publication Date: 2022-09-27T12:40:58Z
• Authors: Kaylee M. Keller; Thomas F. Eleveld; Linda Schild; Kim van den Handel; Marlinde van den ...; Vicky Amo-Addae; Selma Eising; Kimberley Ober; Bianca Koopmans; Leendert Looijenga; Godelieve A.M. Ty...; Bauke Ylstra; Jan J. Molenaar; M. Emmy M. Dolman; Sander R. van Hooff
• Keywords: Synthetic Lethality; CHEK1

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 chromosome 11q MYCN amplification are two genetically distinct subsets neuroblastoma that associated poor patient outcome. Using an isogenic deleted model system high-throughput drug screening, we identify checkpoint kinase 1 (CHK1) as a potential target for neuroblastoma. Further investigation reveals possible additional biomarker CHK1 inhibition, independent loss. Overall, our study highlights power studying chromosomal aberrations to guide preclinical development novel targets combinations. Additionally, builds on growing evidence DNA damage repair replication stress response pathways offer vulnerabilities treatment