Abstract B094: CDK12 inhibition activates cGAS-STING-mediated antitumor immunity and enhances immune checkpoint blockade in basal-like PDAC

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited effective therapies. Using a patient-derived organoid-based drug screen, we identified cyclin-dependent kinase 12 (CDK12) as a promising therapeutic target, particularly in basal-like PDAC. CDK12 is a transcription-associated cyclin-dependent kinase involved in gene expression regulation at multiple levels and has recently gained attention as a therapeutic target in several cancer types. However, the therapeutic impact and potential of CDK12 inhibition in pancreatic cancer remain poorly understood. Both pharmacological and genetic inhibition of CDK12 exerted potent antitumor activity in vitro and in subcutaneous xenograft models using immunodeficient mice, inducing DNA double-strand breaks and apoptosis. To elucidate the underlying antitumor mechanism, we established FKBP12F36V (dTAG) knock-in PDAC cell lines, enabling rapid depletion of endogenous CDK12. Quantitative image-based cytometry and time-lapse imaging revealed that CDK12 ablation induced mitotic arrest followed by DNA damage and apoptosis. Mechanistically, loss of CDK12 kinase activity during S phase perturbed DNA replication, leading to spindle assembly checkpoint activation and subsequent mitotic catastrophe. Furthermore, CDK12 inhibition markedly increased micronuclei formation in vitro, resulting in robust activation of a type I interferon response through the cGAS-STING pathway and increased expression of T-cell-recruiting chemokines. Consistent with these findings, pharmacological inhibition of CDK12 in a syngeneic orthotopic tumor model increased intratumoral CD8+ T-cell infiltration and enhanced the efficacy of combined anti-PD-1 and anti-CTLA-4 therapy. Collectively, our results demonstrate that targeting CDK12 not only induces tumor cell-intrinsic cytotoxicity but also activates antitumor immunity, highlighting the therapeutic potential of combining CDK12 inhibition with immune checkpoint blockade in basal-like PDAC.