Inhibition of CDK10 triggers nucleic acid sensors-mediated anti-tumor

ABSTRACT: Cancer immunotherapies have revolutionized cancer treatment, yet many patients fail to respond. Activating innate immunity in tumors has emerged as a promising strategy to enhance their efficacy. Here, we conduct an in vivo CRISPR screen and identify CDK10 as a key suppressor of tumor immune surveillance. Multi-omics analyses reveal that CDK10 inhibits innate immune pathways mediated by the nucleic sensors MDA5 and cGAS by phosphorylating DNMT1 and RAP80, thereby reducing double-stranded RNA and R-loop formation. Kinase inhibitor screens identify NVP-AST487 and Ponatinib, primarily targeting mutant FLT3 and BCR::ABL1 in leukemia, as potent CDK10 inhibitors. Both genetic and pharmacological inhibition of CDK10 activate MDA5 and cGAS pathways, fostering an immunoactive tumor microenvironment that enhances cancer immunotherapy in multiple mouse tumor models. Clinically, cancer patients with low CDK10 expression in tumors exhibits improved responses to immunotherapies. These findings position CDK10 as a pivotal modulator of tumor immunity and a potential therapeutic target.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Jinfang Zhang  

PROVIDER: PXD059695 | iProX | Sun Jan 12 00:00:00 GMT 2025

REPOSITORIES: iProX