A genetic platform to deconvolve efficacy and toxicity reveals the on-target effects of CDK11 inhibition in vivo
Year: 2026
Type: article
Abstract: ABSTRACT 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 develop MEL-495R, a selective and orally bioavailable CDK11 inhibitor. Additionally, 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 induces widespread on-target toxicity, revealing a narrow therapeutic index. Together, these findings define CDK11 as a core cancer dependency, uncover a chromosomal deletion that sensitizes tumors to CDK11 inhibition, and provide a generalizable strategy for deconvolving drug efficacy and toxicity in vivo for novel oncology targets.
Source: Nature Communications
Authors: Linda Julian, Lisa Crozier, Devon Lukow, Aditi Swamy, Sanat Mishra, Ryan A. Hagenson, Peter Sennhenn, Erin L. Sausville, Amy J. S. McGeoch, Sarah L. Thompson, Brianna Mendelson, Claudio Chuaqui, Lu Qiao, Anand Vasudevan, Kuan-Ting Lin, Sonam Bhatia, Thierry Bertomeu, Andrew Chatr-aryamontri, Li Zhang, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Timothy Nottoli, Suxia Bai, Jayalakshmi Lakshmipathi, Viswanathan Muthusamy, Jonathan G. Van Vranken, Gregory Gauthier-Coles, Steven P. Gygi, Joan C. Smith, Kendall Anderson, Sanjana Shah, Ranjit S. Bindra, Martin Akerman, David L. Spector, Basil J. Greber, Adrian R. Krainer, Jason M. Sheltzer
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Discovering the mechanisms of-action-mistargeted anti-cancer agents, G2702790425, G4373432326, Biochemistry of Pre-mRNA Splicing, G5230563463, G5753238768, G7827448794, G9000142849, G9000279778, Targeting Transcription and Splicing in Cancer, Genomic and functional approaches to characterize Chr1q gains in cancer, Biochemistry of Pre-mRNA Splicing, Cancer Center Support Grant, CSHL Cancer Center Support Grant
OpenAlex ID: W7222954073