Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer

Quereda, Víctor; Bayle, Simon; Vena, Francesca; Frydman, Sylvia M.; Monastyrskyi, Andrii; Roush, William; Duckett, Derek R.

doi:10.1016/j.ccell.2019.09.004

Cited by 214 publications

(228 citation statements)

References 51 publications

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“…PL as a natural product extracted from pepper, which inhibits the expression levels of CDK1 and CDK4/6 and induces G2/M phase cell-cycle arrest to inhibit tumorigenesis [151]. Quereda et al found that SR-4835 is a highly selective dual inhibitor of CDK12 and CDK13, which can inhibit TNBC cell proliferation [80]. Panduratin A (PA) plays multiple roles with anti-inflammatory, antibacterial, antioxidant, and anti-cancer activity.…”

Section: The Novel Cdk Inhibitors In Bcmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

382

261

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Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

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Section: The Novel Cdk Inhibitors In Bcmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

382

261

View full text Add to dashboard Cite

show abstract

“…Tumor suppressor Loss of CDK12 leads to downregulation of DDR 9 genes [61,76] Ovarian cancer (HGSOC 3 ) Tumor suppressor Loss of CDK12 leads to downregulation of DDR 9 genes [21,63,65] Prostate cancer (mCRPC 4 ) Tumor suppressor Loss of CDK12 leads to downregulation of DDR 9 genes [68,69] Gastric cancer Tumor promoter Overexpression of CDK12 actives the CDK12/CCL21 10 pathway [75]…”

Section: Cancer Type Cdk12 S Function Mechanism Referencesmentioning

confidence: 99%

“…Studies have indicated that THZ531 inhibits cell proliferation via preferentially suppressing the expression of DNA repair-related genes and inducing strong DDR in cancer cells [56]. Another novel CDK12/13 inhibitor, SR-4835, has been developed by Quereda's group [76]. It has potential for treatment of TNBC through the downregulation of core DDR genes and upregulation of genes involved in cell apoptosis.…”

Section: Cdk12 As a Potential Target And Biomarker For Cancer Therapymentioning

confidence: 99%

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Liang

et al. 2020

Cells

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Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK12′s biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy.

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“…Cyclin-dependent kinase 12 (CDK12), a member of CDK family, was up-regulated and actively involved in the regulation of chemoresistance in BC. 18 A recent study claimed that CDK12 induced trastuzumab resistance by regulating WNT and IRS1-ErbB-PI3K signaling pathways in BC. 19 Besides, CDK12 down-regulation inhibited de novo and PARP inhibitor resistance in triple-negative BC.…”

Section: Introductionmentioning

confidence: 99%

<p>Long Non-Coding RNA UCA1 Modulates Paclitaxel Resistance in Breast Cancer via miR-613/CDK12 Axis</p>

Liu¹,

Jiang²,

Zhang³

et al. 2020

CMAR

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Background: Paclitaxel (PTX) occupies a considerable status in the chemotherapies of breast cancer (BC), but the drug resistance keeps an obstructive factor of PTX treatment. This study was designed to explore the molecular mechanism of long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) in PTX resistance of BC. Methods: UCA1, microRNA-613 (miR-613) and cyclin-dependent kinase 12 (CDK12) expression was assayed through quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) assay was implemented for evaluating the half inhibitory concentrations (IC 50) of PTX and cell viability. Cell apoptosis was examined by flow cytometry. The target relationship was explored using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. CDK12 protein level was detected through Western blot. Xenograft tumor assay was applied for assessing the influence of UCA1 on PTX resistance of BC in vivo. Results: UCA1 expressed highly in PTX-resistant BC tissues and cells and regulated PTX resistance in BC cells by affecting cell viability and apoptosis in part. UCA1 negatively interacted with miR-613 and modulated PTX resistance via sponging miR-613. CDK12 was a downstream gene of miR-613 and miR-613 exerted the modulation of PTX resistance via targeting CDK12. Furthermore, UCA1 regulated CDK12 level through interacting with miR-613. The regulatory role of UCA1 in PTX resistance of BC was achieved by miR-613/ CDK12 axis in vivo. Conclusion: UCA1 mediated PTX resistance in BC through the miR-613/CDK12 axis, manifesting that UCA1 might improve the PTX treatment of BC as a significant therapeutic biomarker.

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Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer

Cited by 214 publications

References 51 publications

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

<p>Long Non-Coding RNA UCA1 Modulates Paclitaxel Resistance in Breast Cancer via miR-613/CDK12 Axis</p>

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