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

High-risk neuroblastoma remains a leading cause of pediatric cancer mortality, underscoring the need for novel therapeutics. MYCN amplification drives transcriptional addiction, creating vulnerabilities for therapeutic intervention. Inhibition of CDK12, a key regulator of transcription elongation, downregulates DNA damage response (DDR) genes. CDK12 inactivation using protein degraders and small molecules, including the orally bioavailable, selective CDK12/13 inhibitor OKI-1546, induced BRCAness and apoptosis in neuroblastoma cells. High-throughput compound screening combined with CDK12 inhibition/degradation revealed synergistic interactions encompassing multiple biological pathways. Merestinib, a multi-kinase inhibitor, emerged as the top synergistic agent across a panel of neuroblastoma in vitro models. Combining OKI-1546 with merestinib amplified DDR downregulation and diminished MYCN-driven signaling. OKI-1546 treatment reduced tumor growth and extended survival in vivo, which was enhanced when combined with merestinib. Whilst further in vivo validation is warranted, our findings nominate CDK12 as a promising therapeutic target in high-risk neuroblastoma, which can be exploited through combinatorial treatments.