Pharmacologically targeting CDK12 induces BRCAness and synergizes with merestinib to exacerbate DNA damage in high-risk neuroblastoma.

Inhibition of CDK12 induces BRCAness and apoptosis in neuroblastoma cells, with OKI-1546 reducing tumor growth and extending survival in vivo.

• Why it matters: High-risk neuroblastoma has limited treatment options, and MYCN amplification creates vulnerabilities that can be targeted therapeutically. Understanding these vulnerabilities could improve outcomes for this aggressive cancer.
• What they did: Researchers used protein degraders and the selective CDK12/13 inhibitor OKI-1546 to downregulate DNA damage response genes in neuroblastoma cells, and performed high-throughput screening to identify synergistic drug combinations, notably with merestinib.
• The result: Combining OKI-1546 with merestinib amplified DNA damage response downregulation and tumor suppression, suggesting CDK12 as a promising target for combination therapy in high-risk neuroblastoma.