Cell cycle regulation and anticancer drug discovery

Bai, Junwei; Li, Yaochen; Zhang, Guojun

doi:10.20892/j.issn.2095-3941.2017.0033

Cited by 215 publications

(104 citation statements)

References 105 publications

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“…[50] Multiple other studies have shown the role of cell cycle in cancer pathogenesis, and cell cycle regulators are currently being used in the clinic. [51,52]…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

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To understand the molecular differences between right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer, we analyzed colorectal tumors at the DNA, RNA, miRNA and protein levels using previously sequenced data from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center. Clonal evolution analysis identified the same tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor dynamics and selection of downstream mutations were distinct in all three anatomical locations, with some similarities noted between LCC and rectal cancer. We found a potentially targetable alteration APC R1450* specific to RCC that has not been previously described. Differential gene expression analysis revealed multiple genes within the homeobox, G-protein coupled receptor binding and transcription regulation families were dysregulated in RCC, LCC, and rectal cancers and may have a pathological role in these cancers. Further, using a novel in silico proteomic analytic tool developed by our research group, we found distinct central or hub proteins with unique interactomes in each location. Protein expression signatures were not necessarily concordant with the tumor profiles obtained at the DNA and RNA levels, underscoring the relevance of post-transcriptional events in defining the biology of these cancers beyond molecular changes at the DNA and/or RNA level. Ultimately, not only tumor location and the respective genomic profile but also protein-protein interactions will need to be taken into account to improve treatment outcomes of colorectal cancers. Further studies that take into account the alterations found in this study may help in developing more tailored, and perhaps more effective, treatment strategies.Author summaryPatients with right-sided colon cancer (RCC) has a worse prognosis compared to left-sided colon cancer (LCC). Recent data has also shown that wild-type RAS metastatic RCC’s have poor outcomes when treated with the combination of chemotherapy and anti-EGFR therapy compared to LCC and rectal cancers. Therefore, There is an urgent unmet need to understand the molecular differences between RCC, LCC, and rectal cancers. In this study, we demonstrate clonal evolutionary trajectory and the order of mutations in RCC, LCC, and rectal cancers are distinct with some similarities between LCC and rectal cancers. The order of the mutations that lead to the acquisition of crucial driver alterations may have prognostic and therapeutic implications. We also discovered a novel targetable alteration, APC R1450* to be significantly enriched in early, late and metastatic RCC but not in LCC and rectal cancers. Amazingly, proteomic signatures were discordant with DNA and RNA levels. These distinct differences in DNA, RNA and post-transcriptional events may contribute to their unique clinicopathological features.Conflict of Interest StatementAshiq Masood Advisory board and speaker Bureau Bristol-Myers Squibb and Boehringer IngelheimJanakiraman Subramanian Advisory board - Astra Zeneca, Pfizer, Boehringer Ingelheim, Alexion, Paradigm, Bristol-Myers Squibb Speakers Bureau - Astra Zeneca, Boehringer Ingelheim, Lilly Research Support - Biocept and ParadigmArif Hussain Advisory board – Novartis, Bayer, Astra Zeneca Consultant – Bristol-Myers-Squibb All other authors have no conflict of interest.

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“…[50] Multiple other studies have shown the role of cell cycle in cancer pathogenesis, and cell cycle regulators are currently being used in the clinic. [51,52]…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…Cluster2 was featured by enrichment of the majority of genes including CDK4 ( Figure 7A) and lower expression of nc886 ( Figure 7B). Some cancer drugs target cell cycle genes [23]. For example, palbociclib is an FDA-approved CDK4/6 inhibitor.…”

Section: Therapeutic Implication For Escc With Unfavorable Prognosismentioning

confidence: 99%

A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression

Hyun-Sung

Lee

et al. 2020

Cells

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nc886 is a regulatory non-coding RNA (ncRNA) whose expression is frequently silenced in malignancies. In the case of esophageal squamous cell carcinoma (ESCC), nc886 silencing is associated with shorter survival of patients, suggesting nc886’s tumor suppressor role in ESCC. However, this observation has not been complemented by an in-detail study about nc886’s impact on gene expression and cellular phenotypes. Here we have shown that nc886 inhibits AKT, a key protein in a renowned pro-survival pathway in cancer. nc886-silenced cells (nc886− cells) have activated AKT and altered expression of cell cycle genes. nc886− cells tend to have lower expression of CDKN2A and CDKN2C, both of which are inhibitors for cyclin-dependent kinase (CDK), and higher expression of CDK4 than nc886-expressing cells. As a result, nc886− cells are hyperactive in the progression of the G1 to S cell cycle phase, proliferate faster, and are more sensitive to palbociclib, which is a cancer therapeutic drug that targets CDK4/6. Experimentally by nc886 expression and knockdown, we have determined the AKT target genes and cell cycle genes that are controlled by nc886 (nc886-associated gene sets). These gene sets, in combination with pathologic staging and nc886 expression levels, are a vastly superior predictor for the survival of 108 ESCC patients. In summary, our study has elucidated in ESCC how nc886 inhibits cell proliferation to explain its tumor suppressor role and identified gene sets that are of future clinical utility, by predicting patient survival and responsiveness to a therapeutic drug.

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“…CDKs are a family of serine/threonine kinases discovered in yeast, classically shown to promote cell-cycle transitions via interaction with various fluctuating cyclins (75,76). A plethora of evidence suggest that the classical cell cycle CDKs, such as CDK1 and CDK2, are targets for treating various malignancies driven by uncontrolled proliferation (77,78). Interfering with CDK function by targeting CDK regulatory kinases upstream of CDK1/2, such as CHK1 (79) and WEE1 kinase (80), or their combination (81), has also shown proof-of-principle activity in AML (79), and other cancers (82).…”

Section: Cdk Inhibitors As Cancer Therapeuticsmentioning

confidence: 99%

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Tibes

Bogenberger

2019

Front. Oncol.

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Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

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Cell cycle regulation and anticancer drug discovery

Cited by 215 publications

References 105 publications

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

A Regulatory Noncoding RNA, nc886, Suppresses Esophageal Cancer by Inhibiting the AKT Pathway and Cell Cycle Progression

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

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