Dataset Information

Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells.

ABSTRACT:

Background

Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer.

Methods

Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells.

Results

Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent.

Conclusions

Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.

SUBMITTER: Kang J

PROVIDER: S-EPMC3903446 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells.

Kang Jian J Sergio C Marcelo CM Sutherland Robert L RL Musgrove Elizabeth A EA

BMC cancer 20140120

<h4>Background</h4>Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependen ...[more]

PMID: 24444383

Similar Datasets

Project description:Simple Summary Cyclin-dependent kinase 1 (CDK1), one of the key regulators of the G2/M checkpoint, is expressed in many cells and plays an important role in cell cycle control. However, CDK1 expression is substantially increased in many tumors of diverse origins and is associated with tumorigenesis. Targeting CDK1 shows promising results for several tumors. However, a systematic and integrative analysis of CDK1 in cancer has not been conducted. The present study aims to use pan-cancer analysis to investigate the relationship, similarities, and differences in genetic and cellular changes associated with CDK1 in various tumors and tumor microenvironments. Our findings elucidate that CDK1 expression increases in more than 20 human tumors and is highly correlated with oncogenic signature gene sets, biological pathways, immune cell infiltration, tumor mutational burden, microsatellite instability, and lower survival rate across multiple tumors. Targeting CDK1 may provide a novel and effective strategy for cancer immunotherapy. Abstract Cyclin-dependent kinase 1 (CDK1) is essential for cell division by regulating the G2/M phase and mitosis. CDK1 overexpression can also promote the development and progression of a variety of cancers. However, the significance of CDK1 in the formation, progression, and prognosis of human pan-cancer remains unclear. In the present study, we used The Cancer Genome Atlas database, Clinical Proteomic Tumor Analysis Consortium, Human Protein Atlas, Genotype-Tissue Expression, and other well-established databases to comprehensively examine CDK1 genetic alterations and gene/protein expression in various cancers and their relationships with the prognosis, immune reactivities, and clinical outcomes for 33 tumor types. Gene set enrichment analysis was also conducted to examine the potential mechanisms of CDK1 in tumorigenesis. The data showed that CDK1 mutation was frequently present in multiple tumors. CDK1 expression was significantly increased in various types of tumors as compared with normal tissues and was associated with poor overall and disease-free survival. In addition, CDK1 expression was significantly correlated with oncogenic genes, proteins, cellular components, myeloid-derived suppressor cell infiltration, ESTMATEScore, and signaling pathways associated with tumor development and progression and tumor microenvironments. These data indicate that CDK1 could serve as a promising biomarker for predicting tumor prognosis and a potential target for cancer treatment.

Dataset Information

Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells.

Background

Methods

Results

Conclusions

Publications

Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets