CDK12 is established as a tumor suppressor in prostate cancer, with its loss driving aggressive disease and creating vulnerabilities for targeted therapies.
By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Oct 7 2024 Breakthrough research sheds light on the genetic mutation behind aggressive prostate cancer .
Genetic and pharmacologic targeting have shown that the CDK12 transcriptionally regulates DNA damage response genes. Clinical and preclinical data suggest that CDK12 acts as a tumor suppressor in serous ovarian carcinoma and triple-negative breast cancer. To describe more explicitly how the loss of CDK12 promoted tumorigenesis, investigators generated organoids from purified populations of prostate epithelial cells lacking CDK12. Utilizing the organoid model of prostate cancer, investigators performed clustered regularly interspaced short palindromic repeats screening to identify mutations that either interacted positively or negatively with the loss of CDK12.
Given the link between CDK12 loss and castration resistance in human PCa, investigators analyzed androgen receptor signaling in CDK12KO organoids. Results CDK12 loss characterizes a mCRPC subtype. The study demonstrated that CD12 suppresses prostate cancers, and its loss drives AR and myelocytomatosis proto-oncogene -regulated hypertranscription. CDK12 loss causes TRCs that induce DNA damage, as demonstrated by DRB treatment and γH2AX immunohistochemistry.
Prostate Breast Cancer Cancer Carcinoma Cell Cell Cycle CRISPR Cyclin-Dependent Kinase DNA DNA Damage Enzyme Gene Gene Expression Genes Genetic Immunohistochemistry Kinase Knockout Medicine Mutation Organoids Preclinical Prostate Cancer Protein Research Ribonucleic Acid Transcription Tumor Tumorigenesis
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