CDK7 in Breast Cancer: Mechanisms of Action and Therapeutic Potential

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 Apr 11

PMID 38605321

Authors

Ying Gong

Huiping Li

Affiliations

Soon will be listed here.

Abstract

Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.

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References

Siegel R, Miller K, Jemal A . Cancer statistics, 2020. CA Cancer J Clin. 2020; 70(1):7-30. DOI: 10.3322/caac.21590. View

Patel H, Abduljabbar R, Lai C, Periyasamy M, Harrod A, Gemma C . Expression of CDK7, Cyclin H, and MAT1 Is Elevated in Breast Cancer and Is Prognostic in Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2016; 22(23):5929-5938. PMC: 5293170. DOI: 10.1158/1078-0432.CCR-15-1104. View

St Amour C, Sanso M, Bosken C, Lee K, Larochelle S, Zhang C . Separate domains of fission yeast Cdk9 (P-TEFb) are required for capping enzyme recruitment and primed (Ser7-phosphorylated) Rpb1 carboxyl-terminal domain substrate recognition. Mol Cell Biol. 2012; 32(13):2372-83. PMC: 3434489. DOI: 10.1128/MCB.06657-11. View

Zhang W, Ge H, Jiang Y, Huang R, Wu Y, Wang D . Combinational therapeutic targeting of BRD4 and CDK7 synergistically induces anticancer effects in head and neck squamous cell carcinoma. Cancer Lett. 2019; 469:510-523. DOI: 10.1016/j.canlet.2019.11.027. View

Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P . Breast cancer. Nat Rev Dis Primers. 2019; 5(1):66. DOI: 10.1038/s41572-019-0111-2. View

Valenciaga A, Saji M, Yu L, Zhang X, Bumrah C, Yilmaz A . Transcriptional targeting of oncogene addiction in medullary thyroid cancer. JCI Insight. 2018; 3(16). PMC: 6141185. DOI: 10.1172/jci.insight.122225. View

Attia Y, Shouman S, Salama S, Ivan C, Elsayed A, Amero P . Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer. Int J Mol Sci. 2020; 21(8). PMC: 7215326. DOI: 10.3390/ijms21082974. View

Larochelle S, Merrick K, Terret M, Wohlbold L, Barboza N, Zhang C . Requirements for Cdk7 in the assembly of Cdk1/cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol Cell. 2007; 25(6):839-50. PMC: 1858677. DOI: 10.1016/j.molcel.2007.02.003. View

Galbraith M, Bender H, Espinosa J . Therapeutic targeting of transcriptional cyclin-dependent kinases. Transcription. 2018; 10(2):118-136. PMC: 6602565. DOI: 10.1080/21541264.2018.1539615. View

10.

Gao Y, Volegova M, Nasholm N, Das S, Kwiatkowski N, Abraham B . Synergistic Anti-Tumor Effect of Combining Selective CDK7 and BRD4 Inhibition in Neuroblastoma. Front Oncol. 2022; 11:773186. PMC: 8859926. DOI: 10.3389/fonc.2021.773186. View

11.

Chen D, Zhao Z, Huang Z, Chen D, Zhu X, Wang Y . Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma. Bone Res. 2018; 6:11. PMC: 5884797. DOI: 10.1038/s41413-018-0009-8. View

12.

Kovalova M, Baraka J, Mik V, Jorda R, Luo L, Shao H . A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022). Expert Opin Ther Pat. 2023; 33(2):67-87. DOI: 10.1080/13543776.2023.2195547. View

13.

Gonzalez-Ericsson P, Stovgaard E, Sua L, Reisenbichler E, Kos Z, Carter J . The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice. J Pathol. 2020; 250(5):667-684. DOI: 10.1002/path.5406. View

14.

Kalan S, Amat R, Schachter M, Kwiatkowski N, Abraham B, Liang Y . Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors. Cell Rep. 2017; 21(2):467-481. PMC: 5687273. DOI: 10.1016/j.celrep.2017.09.056. View

15.

Zhou Y, Lu L, Jiang G, Chen Z, Li J, An P . Targeting CDK7 increases the stability of Snail to promote the dissemination of colorectal cancer. Cell Death Differ. 2018; 26(8):1442-1452. PMC: 6748077. DOI: 10.1038/s41418-018-0222-4. View

16.

Zhang J, Liu W, Zou C, Zhao Z, Lai Y, Shi Z . Targeting Super-Enhancer-Associated Oncogenes in Osteosarcoma with THZ2, a Covalent CDK7 Inhibitor. Clin Cancer Res. 2020; 26(11):2681-2692. DOI: 10.1158/1078-0432.CCR-19-1418. View

17.

Fillmore C, Gupta P, Rudnick J, Caballero S, Keller P, Lander E . Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci U S A. 2010; 107(50):21737-42. PMC: 3003123. DOI: 10.1073/pnas.1007863107. View

18.

Sun J, Zhang Q, Sun X, Xue A, Gao X, Shen K . THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours. Cell Commun Signal. 2022; 20(1):138. PMC: 9454178. DOI: 10.1186/s12964-022-00928-x. View

19.

Tang L, Jin J, Xu K, Wang X, Tang J, Guan X . SOX9 interacts with FOXC1 to activate MYC and regulate CDK7 inhibitor sensitivity in triple-negative breast cancer. Oncogenesis. 2020; 9(5):47. PMC: 7217837. DOI: 10.1038/s41389-020-0232-1. View

20.

Garralda E, Schram A, Bedard P, Schwartz G, Yuen E, McNeely S . A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors. Oncologist. 2023; 29(1):e131-e140. PMC: 10769797. DOI: 10.1093/oncolo/oyad215. View