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

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.

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

“…The FDA has granted fast track designations to prexasertib in platinum-resistant ovarian cancer and endometrial cancer as monotherapy or in combination with low-dose gemcitabine (NCT05548296). As MYCN amplification has been shown to increase RS it is considered as a possible additional biomarker for use of CHK1i like prexasertib in neuroblastoma [150]. Prexasertib was tested either as a single agent or in combination with PARPi olaparib in serous carcinoma PDX models and in a panel of ovarian cancer cell lines [141,151,152].…”