Targeting CDK12 in Neuroblastoma Cells

Background

Neuroblastoma (NB) is the leading cause of cancer-related death in children. Despite intensive treatment regimens approximately 50-60% of patients with high-risk neuroblastoma will eventually relapse, emphasizing the need for novel treatment approaches.

The aim of my project is to test the feasibility of using a novel inhibitor against cyclin-dependent kinase 12 (CDK 12) as a therapeutic strategy. Cyclin-dependent kinases (CDKs) encode proteins that regulate cell division and gene expression (transcription). CDKs whose primary roles involve transcription are emerging as potential therapeutic targets in cancer.

THZ1, a covalent inhibitor of CDK7, induces a striking selective antitumor effect in neuroblastoma cells driven by MYCN amplification. Similarly, inhibition of CDK12, with a novel small molecule compound (THZ-5-31-1) induces potent cell kill in neuroblastoma cells. CDK12 regulates the expression of genes involved in DNA damage response (DDR) - a mechanism by which cells protect themselves against various insults such as radiation and chemotherapeutic agents.

Project Goal

The George laboratory has found that CDK12 inhibition leads to impaired DDR in neuroblastoma cells. However, the direct role of CDK12 in the regulation of DDR has not been fully addressed. I will investigate the molecular mechanism of CDK12 inhibition and its effect on DDR. I will also test potential therapeutic combinations of CDK12 inhibition with standard therapy regimens. Altogether, the proposed study is aimed to provide a preclinical rationale for further therapeutic development of CDK12 inhibitors.