New insights into the dule roles CDK12 in human cancers: Mechanisms and interventions for cancer therapy

The dysregulation of cyclin-dependent kinase 12 (CDK12), which may result from genomic alterations or modulation by upstream effectors, is implicated in cancer oncogenesis and progression. CDK12 overexpression or activation is sufficient to induce tumor initiation, recurrence, and therapeutic resistance. However, CDK12 may also exert tumor-suppressive functions in a context-dependent manner. Therefore, caution is warranted when targeting CDK12 in future clinical trials. A comprehensive elucidation of the dual roles and underlying mechanisms of CDK12 in carcinogenesis is urgently needed to advance precision oncology. This review provides an overview of the current understanding of the dysregulation and biological roles of CDK12 in cancer. Subsequently, we systematically summarize the functions and mechanisms of the oncogenic and tumor-suppressive roles of CDK12 in different contexts. Finally, we discuss the potential of CDK12 as a novel therapeutic target and its implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.

• Publication year

  2024

• Venue

  Journal of Pharmaceutical Analysis

• Publication date

  2024-12-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1016/j.jpha.2024.101173PMID 40747342PMCID 12311446
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts

  2024cited by this paper
• Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets

  2024cited by this paper
• Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition

  2024cited by this paper
• Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects

  2024cited by this paper
• CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in colorectal cancer.

  2024cited by this paper
• CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13

  2024cited by this paper
• CDK12 regulates angiogenesis of advanced prostate cancer by IGFBP3

  2024cited by this paper
• Cyclin‐dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration‐resistant prostate cancer

  2024cited by this paper
• NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness

  2024cited by this paper
• CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer

  2024cited by this paper
• Targeting Super-Enhancer-Driven Transcriptional Dependencies Suppresses Aberrant Hedgehog Pathway Activation and Overcomes Smoothened Inhibitor Resistance.

  2024cited by this paper
• Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader

  2024cited by this paper
• Evaluating Immune Checkpoint Blockade in Metastatic Castration-Resistant Prostate Cancers with Deleterious CDK12 Alterations in the Phase 2 IMPACT Trial.

  2024cited by this paper
• Abstract 3301: Translational research of CDK12/13 inhibitor, CTX-439, informing clinical trial strategy

  2024cited by this paper
• AR-A014418 regulates intronic polyadenylation and transcription of PD-L1 through inhibiting CDK12 and CDK13 in tumor cells

  2023cited by this paper
• Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13

  2023cited by this paper
• MYC up-regulation confers vulnerability to dual inhibition of CDK12 and CDK13 in high-risk Group 3 medulloblastoma

  2023cited by this paper
• CDK12 Promotes the Proliferation, Migration, and Angiogenesis of Gastric Carcinoma via Activating the PI3K/AKT/mTOR Signaling Pathway

  2023cited by this paper
• CDK12/13 promote splicing of proximal introns by enhancing the interaction between RNA polymerase II and the splicing factor SF3B1

  2023cited by this paper
• Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer.

  2023cited by this paper
• Is euchromatin really open in the cell?

  2023cited by this paper
• The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma

  2023cited by this paper
• Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids

  2023cited by this paper
• Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/β-catenin signaling pathway.

  2023cited by this paper
• Hallmarks of Cancer: New Dimensions.

  2022cited by this paper
• The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells

  2022cited by this paper
• CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma

  2022cited by this paper
• CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer

  2022influential reference
• Chemical inhibitors of transcription-associated kinases.

  2022cited by this paper
• Current progress and novel strategies that target CDK12 for drug discovery.

  2022cited by this paper
• 3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.

  2022cited by this paper
• Abstract 5485: Discovery and preclinical evaluation of a novel highly selective and potent CDK12 inhibitor

  2022cited by this paper
• PROTACs: past, present and future.

  2022cited by this paper
• CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer

  2022cited by this paper
• Proteolysis-targeting chimeras (PROTACs) in cancer therapy

  2022cited by this paper
• OUP accepted manuscript

  2022cited by this paper
• UALCAN: An update to the integrated cancer data analysis platform

  2022cited by this paper
• Structure and Function of ATP-dependent Chromatin Remodeling Complexes.

  2021cited by this paper
• MYC as a target for cancer treatment.

  2021cited by this paper
• Alternative polyadenylation: An untapped source for prostate cancer biomarkers and therapeutic targets?

  2021cited by this paper
• Comprehensive analysis of metastatic gastric cancer tumour cells using single-cell RNA-seq

  2021cited by this paper
• Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer.

  2021cited by this paper
• Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma.

  2021cited by this paper
• Discovery and resistance mechanism of a selective CDK12 degrader

  2021cited by this paper
• CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT.

  2021cited by this paper
• Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas

  2021cited by this paper
• CDK12 is Necessary to Promote Epidermal Differentiation through Transcription Elongation

  2021cited by this paper
• Advancing targeted protein degradation for cancer therapy

  2021cited by this paper
• Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor.

  2021cited by this paper
• Long Non-Coding RNA UCA1 Modulates Paclitaxel Resistance in Breast Cancer via miR-613/CDK12 Axis

  2020cited by this paper
• Reprogramming of serine, glycine and one-carbon metabolism in cancer.

  2020cited by this paper
• TIMER2.0 for analysis of tumor-infiltrating immune cells

  2020cited by this paper
• Low expression of CDK12 in gastric cancer is correlated with advanced stage and poor outcome.

  2020cited by this paper
• CDK12 and PAK2 as novel therapeutic targets for human gastric cancer

  2020cited by this paper
• The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

  2020cited by this paper
• Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13.

  2020cited by this paper
• Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation

  2020cited by this paper
• CDK12-Mutated Prostate Cancer: Clinical Outcomes With Standard Therapies and Immune Checkpoint Blockade.

  2020cited by this paper
• CDK12: A Potent Target and Biomarker for Human Cancer Therapy

  2020cited by this paper
• Cyclin E2 Promotes Whole Genome Doubling in Breast Cancer

  2020cited by this paper
• CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer.

  2020cited by this paper
• Targeting CDK12 for Cancer Therapy: Function, Mechanism, and Drug Discovery

  2020cited by this paper
• CDK12: a potential therapeutic target in cancer.

  2020cited by this paper
• CDK12 Deficiency and the Immune Microenvironment in Prostate Cancer

  2020cited by this paper
• Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy.

  2020cited by this paper
• CDK12: cellular functions and therapeutic potential of versatile player in cancer

  2020cited by this paper
• Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics.

  2020cited by this paper
• CDK12 promotes papillary thyroid cancer progression through regulating the c-myc/β-catenin pathway

  2020cited by this paper
• Angiogenesis and vasculogenic mimicry as therapeutic targets in ovarian cancer

  2020cited by this paper
• Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma.

  2019cited by this paper
• BRCA1 Deficiency Upregulates NNMT Which Reprograms Metabolism and Sensitizes Ovarian Cancer Cells to Mitochondrial Metabolic Targeting Agents.

  2019cited by this paper
• Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer.

  2019cited by this paper
• Pan-Cancer Analysis of CDK12 Loss-of-Function Alterations and Their Association with the Focal Tandem-Duplicator Phenotype.

  2019cited by this paper
• GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis

  2019cited by this paper
• CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability

  2019cited by this paper
• Tumor angiogenesis: causes, consequences, challenges and opportunities

  2019cited by this paper
• Induction of BRCAness in Triple-Negative Breast Cancer by a CDK12/13 Inhibitor Improves Chemotherapy.

  2019cited by this paper
• A view on drug resistance in cancer

  2019cited by this paper
• CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

  2019influential reference
• CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1‐ErbB‐PI3K signaling

  2019influential reference
• Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma.

  2019cited by this paper
• CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma

  2019cited by this paper
• Targeting mRNA processing as an anticancer strategy

  2019cited by this paper
• Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13

  2018cited by this paper
• EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.

  2018cited by this paper
• Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

  2018cited by this paper
• Current status and future directions of cancer immunotherapy

  2018cited by this paper
• Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation

  2018cited by this paper
• Structure‐Based Design of Selective Noncovalent CDK12 Inhibitors

  2018cited by this paper
• Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes

  2018cited by this paper
• Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer.

  2018cited by this paper
• CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling

  2018cited by this paper
• Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors.

  2018cited by this paper
• Interplay between YAP/TAZ and Metabolism.

  2018cited by this paper
• CDK12: an emerging therapeutic target for cancer

  2018cited by this paper
• Widespread intronic polyadenylation inactivates tumor suppressor genes in leukemia

  2018cited by this paper
• Cyclin‐Dependent Kinase 12, Immunity, and Prostate Cancer

  2018cited by this paper
• Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis

  2018cited by this paper
• Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium

  2018cited by this paper
• Cdk12 regulates DNA repair genes by suppressing intronic polyadenylation

  2018cited by this paper

• CDK12 Paradox in Breast Cancer: Loss-of-Function Fusion and Oncogenic Amplification as Dual Therapeutic Targets.

  2026cites this paper
• Cancer Stemness and Dedifferentiation in Anaplastic Thyroid Carcinoma: Insights into a Multigenic, Microenvironmental Network and the Role of CD44.

  2026cites this paper
• DNA-Encoded Library Screening Identifies CDK2-Targeting Lead Compounds with Favorable Drug-like Properties for Anticancer Development

  2025cites this paper