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Life sciences · Journal article
Nature Communications · October 19, 2026
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The cyclin-dependent kinase CDK11 is an understudied kinase that has been the subject of conflicting reports regarding its function in cancer. Here, we combine genetic and pharmacological approaches to demonstrate that CDK11 is a critical regulator of cancer cell survival that is required for RNA splicing and the expression of homologous recombination genes. Inhibition of CDK11 disrupts genome stability, promotes the retention of intronic sequences in mature mRNAs, and induces synthetic lethality with PARP inhibitors. Through integrative analysis of functional genomics datasets, we identify heterozygous deletions of chromosome 1p36 - which encompasses CDK11 and its activating cyclin CCNL2 - as a recurrent and predictive biomarker of sensitivity to CDK11 inhibition. To assess the therapeutic potential of CDK11, we establish a genetically-engineered mouse model that allows us to differentiate between the on-target and off-target effects of CDK11 inhibitors in vivo. Using this platform, we demonstrate that MEL-495R, an orally bioavailable CDK11 inhibitor, induces widespread on-target toxicity, revealing a narrow therapeutic index. Experiments with a chemically distinct CDK11 inhibitor similarly reveal minimal anti-cancer activity at tolerable doses. Together, these findings define CDK11 as a core cancer dependency, uncover a chromosomal deletion that sensitizes tumors to CDK11 inhibition, demonstrate that on-target toxicity limits the efficacy of CDK11-targeting therapies, and provide a generalizable strategy for deconvolving drug efficacy and toxicity in vivo for novel oncology targets. CDK11 encodes a poorly-characterized cyclin-dependent kinase. Here, the authors demonstrate that CDK11 is essential for cancer proliferation, but the function(s) of CDK11 in normal tissue limits the efficacy of CDK11 inhibition as a therapeutic strategy.