Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2

Weiswald, Louis‐Bastien; Hasan, Mohammad Rubayet; Wong, Johnathan; Pasiliao, Clarissa C.; Rahman, Mahbuba; Ren, Jianhua; Yin, Yongjun; Gusscott, Samuel; Vacher, Sophie; Weng, Andrew P.; Kennecke, Hagen F.; Bièche, Ivan; Schaeffer, David F.; Yapp, Donald T.; Tai, Isabella T.

doi:10.1158/1535-7163.mct-16-0666

Cited by 14 publications

(23 citation statements)

References 41 publications

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“…CDK10 small-molecule inhibitors would complement the classical reverse genetics toolbox in exploring biological functions of this protein kinase. They may also confirm the therapeutic interest of CDK10/CycM as a target in colorectal adenocarcinomas, as recently suggested by a reverse genetics approach (Weiswald et al, 2017). However, to date, no screening assays or inhibitors for CDK10 have been reported.…”

Section: Introductionsupporting

confidence: 69%

“…Although a recent study argued that CDK10 is a candidate therapeutic target for colorectal adenocarcinomas (Weiswald et al, 2017), a number of reports indicate that CDK10 acts as a tumor suppressor in various cancers of the digestive system, including biliary tract cancer , hepatocellular carcinomas , gastric carcinomas (Zhao et al, 2017;You et al, 2018), and in nasopharyngeal carcinomas (You et al, 2013), gliomas (Li et al, 2018) and advanced breast cancers (You et al, 2015). These contradictory findings could be explained by the fact that ETS2, whose stability is controlled in part by CDK10/CycM phosphorylation (Guen et al, 2013), can function either as an oncogene or a tumor suppressor depending on various factors such as cellular context and p53 status (Martinez, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

et al. 2020

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Cyclin-dependent kinases (CDKs) constitute a family of 20 serine/threonine protein kinases that play pivotal roles in the regulation of numerous important molecular and cellular processes. CDKs have long been considered promising therapeutic targets in a variety of pathologies, and the recent therapeutic success of CDK4/6 inhibitors in breast cancers has renewed interest in their therapeutic potential. Small-molecule inhibitors have been identified for every human CDK, except for CDK10. The only recent discovery of an activating cyclin (CycM) for CDK10 enabled us to identify its first phosphorylation substrates and gain insights into its biological functions. Yet, our knowledge of this kinase remains incomplete, despite it being the only member of its family that causes severe human developmental syndromes, when mutated either on the cyclin or the CDK moiety. CDK10 small-molecule inhibitors would be useful in exploring the functions of this kinase and gauging its potential as a therapeutic target for some cancers. Here, we report the identification of an optimized peptide phosphorylation substrate of CDK10/CycM and the development of the first homogeneous, miniaturized CDK10/CycM in vitro kinase assay. We reveal the ability of known CDK inhibitors, among which clinically tested SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573 and AT7519, to potently inhibit CDK10/CycM. We also show that NVP-2, a strong, remarkably selective CDK9 inhibitor is an equally potent CDK10/CycM inhibitor. Finally, we validate this kinase assay for applications in high-throughput screening campaigns to discover new, original CDK10 inhibitors.

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Section: Introductionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

et al. 2020

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“…In particular, many genes identified by our analysis, including WNT3, SLC22A3 (MIM: 604842), PCAT19 (MIM: 618192), CEACAM21 (MIM: 618191), and CABLES2, have been verified by in vitro or in vivo experiments to be involved in cell growth, proliferation, and apoptosis. [65][66][67][68][69][70][71] It should be noted that a total of 16 identified eQTL target genes, five in lung adenocarcinoma and 11 in prostate cancer, showed inconsistent direction of association in previous literature 18,19 (Table S2).…”

Section: Discussionmentioning

confidence: 91%

Identifying Putative Susceptibility Genes and Evaluating Their Associations with Somatic Mutations in Human Cancers

Chen

Wen

Beeghly–Fadiel

et al. 2019

The American Journal of Human Genetics

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Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer-colorectal, lung, ovary, prostate, pancreas, and melanoma-by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.

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“…Function of ZNF767, which is also edge gene of AHSA2 in our data, and SECISBP2L has not been studied yet. CDK10, cyclin dependent kinase 10, has been reported high expression in colon cancer and inactivation of its kinase domain showed prevention of tumor growth lately 22 . CWC22, the other upregulated hub genes in the LN(+) group, is a CWC22 spliceosome associated protein and has been suggested to be an unfavorable prognostic marker in renal and liver cancer (https://www.proteinatlas.org/ENSG00000163510-CWC22/pathology), although its function still needs to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Gene expression network analysis of lymph node involvement in colon cancer identifies AHSA2, CDK10, and CWC22 as possible prognostic markers

Han

Ahn

Lee

et al. 2020

Sci Rep

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Colon cancer has been well studied using a variety of molecular techniques, including whole genome sequencing. However, genetic markers that could be used to predict lymph node (LN) involvement, which is the most important prognostic factor for colon cancer, have not been identified. In the present study, we compared LN(+) and LN(−) colon cancer patients using differential gene expression and network analysis. Colon cancer gene expression data were obtained from the Cancer Genome Atlas and divided into two groups, LN(+) and LN(−). Gene expression networks were constructed using LASSO (Least Absolute Shrinkage and Selection Operator) regression. We identified hub genes, such as APBB1, AHSA2, ZNF767, and JAK2, that were highly differentially expressed. Survival analysis using selected hub genes, such as AHSA2, CDK10, and CWC22, showed that their expression levels were significantly associated with the survival rate of colon cancer patients, which indicates their possible use as prognostic markers. In addition, protein-protein interaction network, GO enrichment, and KEGG pathway analysis were performed with selected hub genes from each group to investigate the regulatory relationships between hub genes and LN involvement in colon cancer; these analyses revealed differences between the LN(−) and LN(+) groups. Our network analysis may help narrow down the search for novel candidate genes for the treatment of colon cancer, in addition to improving our understanding of the biological processes underlying LN involvement. All R implementation codes are available at journal website as Supplementary Materials.

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Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2

Cited by 14 publications

References 41 publications

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

Identifying Putative Susceptibility Genes and Evaluating Their Associations with Somatic Mutations in Human Cancers

Gene expression network analysis of lymph node involvement in colon cancer identifies AHSA2, CDK10, and CWC22 as possible prognostic markers

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