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

Kaylee M Keller; Thomas F Eleveld; Linda Schild; Kim van den Handel; Marlinde van den Boogaard; Vicky Amo-Addae; Selma Eising; Kimberley Ober; Bianca Koopmans; Leendert Looijenga; Godelieve A M Tytgat; Bauke Ylstra; Jan J Molenaar; M Emmy M Dolman; Sander R van Hooff

doi:10.3389/fonc.2022.929123

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

Front Oncol. 2022 Sep 27:12:929123. doi: 10.3389/fonc.2022.929123. eCollection 2022.

Authors

Kaylee M Keller¹, Thomas F Eleveld¹, Linda Schild¹, Kim van den Handel¹, Marlinde van den Boogaard¹, Vicky Amo-Addae¹, Selma Eising¹, Kimberley Ober¹, Bianca Koopmans¹, Leendert Looijenga¹, Godelieve A M Tytgat¹, Bauke Ylstra², Jan J Molenaar^{1

3}, M Emmy M Dolman^{1

4

5}, Sander R van Hooff¹

Affiliations

¹ Department of Research, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
² Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, Netherlands.
³ Department of Pharmaceutical Sciences, University Utrecht, Utrecht, Netherlands.
⁴ Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.
⁵ School of Women's and Children's Health, Faculty of Medicine, UNSW Sydney, Kensington, NSW, Australia.

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.

Keywords: MYCN amplification; checkpoint kinase 1 (CHK1); chromosome 11q deletion; neuroblastoma; pediatric cancer; prexasertib; replication stress; synergy.