Cyclin-dependent kinases in breast cancer: expression pattern and therapeutic implications

Sofi, Shazia; Mehraj, Umar; Qayoom, Hina; Aisha, Shariqa; Asdaq, Syed Mohammad Basheeruddin; Almilaibary, Abdullah; Mir, Manzoor Ahmad

doi:10.1007/s12032-022-01731-x

Cited by 62 publications

(24 citation statements)

References 97 publications

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“…Moreover, therapeutic regimens used in combination may act in a synergistic manner reducing the drug dose required as well as reducing the toxicities associated with chemotherapy [ 51 ]. Targeting CDKs in combination with conventional therapeutic regimens is a promising approach, given the role of CDKs in cancer [ 12 ]. Thus, there is an urgent need to identify therapeutic agents specifically targeting CDKs in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…The cell cycle is a highly conserved and tightly controlled cell process regulated by checkpoints, cyclin-dependent kinases (CDKs), and cyclins [ 8 , 9 ]. Alterations in the regulatory mechanisms result in loss of the cell cycle control system and subsequently uncontrolled proliferation of cells, which ultimately leads to tumor formation [ 10 – 12 ]. Moreover, cell proliferation being the requisite process for the development of tumors, targeting cell cycle regulatory proteins is a promising therapeutic strategy [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

et al. 2022

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Cell cycle dysregulation is a characteristic hallmark of malignancies, which results in uncontrolled cell proliferation and eventual tumor formation. Cyclin-dependent kinase 1 (CDK1) is a member of the family of cell cycle regulatory proteins involved in cell cycle maintenance. Given that overexpression of CDK1 has been associated with cancer, CDK1 inhibitors may restore equilibrium to the skewed cell cycle system and operate as an effective therapeutic drug. This study aimed to identify and classify inhibitors having a higher affinity for CDK1 and also evaluate the expression pattern and prognostic relevance of CDK1 in a wide range of cancers. We investigated therapeutic molecules structurally similar to dinaciclib for their ability to inhibit CDK1 selectively. To assess the therapeutic potential of screened Dinaciclib analogs, we used drug likeliness analysis, molecular docking, and simulation analysis. CDK1 was found to be highly upregulated across several malignancies and is associated with poor overall and relapse-free survival. Molecular docking and dynamics evaluation identified two novel dinaciclib analogs as potent CDK1 inhibitors with high binding affinity and stability compared to dinaciclib. The results indicate that increased CDK1 expression is associated with decreased OS and RFS. Additionally, dinaciclib analogs are prospective replacements for dinaciclib since they exhibit increased binding affinity, consistent with MDS findings, and have acceptable ADMET qualities. The discovery of new compounds may pave the road for their future application in cancer prevention through basic, preclinical, and clinical research. Supplementary Information The online version contains supplementary material available at 10.1007/s12032-022-01748-2.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

et al. 2022

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“…In addition to its enhanced ability to inhibit proliferation and promote tumor cell apoptosis, ADA may offer numerous advantages over conventional retinoic acid derivatives in vivo , such as increased stability, more prolonged comedolytic action, enhanced anti-inflammatory activity, and a favorable safety profile ( Ocker et al, 2003 ; Shi et al, 2015 ; Ghosalkar et al, 2018 ; Rusu et al, 2020 ; Sofi et al, 2022b ).…”

Section: Discussionmentioning

confidence: 99%

Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

et al. 2022

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Although advances in diagnostics and therapeutics have prolonged the survival of triple-negative breast cancer (TNBC) patients, metastasis, therapeutic resistance, and lack of targeted therapies remain the foremost hurdle in the effective management of TNBC. Thus, evaluation of new therapeutic agents and their efficacy in combination therapy is urgently needed. The third-generation retinoid adapalene (ADA) has potent antitumor activity, and using ADA in combination with existing therapeutic regimens may improve the effectiveness and minimize the toxicities and drug resistance. The current study aimed to assess the anticancer efficacy of adapalene as a combination regimen with the PI3K inhibitor (GDC-0941) in TNBC in vitro models. The Chou–Talalay’s method evaluated the pharmacodynamic interactions (synergism, antagonism, or additivity) of binary drug combinations. Flow cytometry, Western blotting, and in silico studies were used to analyze the mechanism of GDC–ADA synergistic interactions in TNBC cells. The combination of GDC and ADA demonstrated a synergistic effect in inhibiting proliferation, migration, and colony formation of tumor cells. Accumulation of reactive oxygen species upon co-treatment with GDC and ADA promoted apoptosis and enhanced sensitivity to GDC in TNBC cells. The findings indicate that ADA is a promising therapeutic agent in treating advanced BC tumors and enhance sensitivity to GDC in inhibiting tumor growth in TNBC models while reducing therapeutic resistance.

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“…As discussed earlier, the glycolytic phenotype promotes the proliferation, migration, and invasion of TNBC cells. Deregulation of the cell cycle is also a hallmark of cancer that enables limitless cell division and is frequently observed in breast cancer (Thu et al, 2018;Sofi et al, 2022). Therefore, the pathway difference may also explain the prognosis difference between the high-risk and low-risk groups.…”

Section: Discussionmentioning

confidence: 99%

Identification of ubiquitination-related gene classification and a novel ubiquitination-related gene signature for patients with triple-negative breast cancer

Zhao

Zheng

et al. 2023

Front. Genet.

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Background: Ubiquitination-related genes (URGs) are important biomarkers and therapeutic targets in cancer. However, URG prognostic prediction models have not been established in triple-negative breast cancer (TNBC) before. Our study aimed to explore the roles of URGs in TNBC.Methods: The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and the Gene Expression Omnibus (GEO) databases were used to identify URG expression patterns in TNBC. Non-negative matrix factorization (NMF) analysis was used to cluster TNBC patients. The least absolute shrinkage and selection operator (LASSO) analysis was used to construct the multi-URG signature in the training set (METABRIC). Next, we evaluated and validated the signature in the test set (GSE58812). Finally, we evaluated the immune-related characteristics to explore the mechanism.Results: We identified four clusters with significantly different immune signatures in TNBC based on URGs. Then, we developed an 11-URG signature with good performance for patients with TNBC. According to the 11-URG signature, TNBC patients can be classified into a high-risk group and a low-risk group with significantly different overall survival. The predictive ability of this 11-URG signature was favorable in the test set. Moreover, we constructed a nomogram comprising the risk score and clinicopathological characteristics with favorable predictive ability. All of the immune cells and immune-related pathways were higher in the low-risk group than in the high-risk group.Conclusion: Our study indicated URGs might interact with the immune phenotype to influence the development of TNBC, which contributes to a further understanding of molecular mechanisms and the development of novel therapeutic targets for TNBC.

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Cyclin-dependent kinases in breast cancer: expression pattern and therapeutic implications

Cited by 62 publications

References 97 publications

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors

Adapalene inhibits the growth of triple-negative breast cancer cells by S-phase arrest and potentiates the antitumor efficacy of GDC-0941

Identification of ubiquitination-related gene classification and a novel ubiquitination-related gene signature for patients with triple-negative breast cancer

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