The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen

Riggs, Jennifer R.; Nagy, Mark A.; Elsner, Jan; Erdman, Paul; Cashion, Dan; Robinson, Dale; Harris, Roy; Huang, Dehua; Tehrani, Lida; Deyanat-Yazdi, Gordafaried; Narla, Rama Krishna; Peng, Xiaohui; Tran, Tam; Barnes, Leo A.; Miller, Terra; Katz, Jason D.; Tang, Yang; Chen, Ming; Moghaddam, Mehran F.; Bahmanyar, Sogole; Pagarigan, Barbra; Delker, S.L.; LeBrun, Laurie A.; Chamberlain, Philip P.; Calabrese, Andrew; Canan, Stacie; Leftheris, Katerina; Zhu, Dan; Boylan, John F.

doi:10.1021/acs.jmedchem.7b01223

Cited by 50 publications

(52 citation statements)

References 33 publications

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“…At present, many studies have found that high expression of dual specificity protein kinase (TTK), encoded by the TTK gene, is associated with the oncogenesis, progression and treatment resistance of breast cancer (especially TNBC) (Riggs et al, 2017). It was reported that TTK could regulate the growth and epithelial-to-mesenchymal transition of TNBC cells through TGF-β and KLF5 signal pathways, thereby affecting the invasion and metastasis of tumors (King et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Differentially expressed genes and key molecules of BRCA1/2-mutant breast cancer: evidence from bioinformatics analyses

Zhou

Liu

et al. 2020

PeerJ

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Background BRCA1 and BRCA2 genes are currently proven to be closely related to high lifetime risks of breast cancer. To date, the closely related genes to BRCA1/2 mutations in breast cancer remains to be fully elucidated. This study aims to identify the gene expression profiles and interaction networks influenced by BRCA1/2 mutations, so as to reflect underlying disease mechanisms and provide new biomarkers for breast cancer diagnosis or prognosis. Methods Gene expression profiles from The Cancer Genome Atlas (TCGA) database were downloaded and combined with cBioPortal website to identify exact breast cancer patients with BRCA1/2 mutations. Gene set enrichment analysis (GSEA) was used to analyze some enriched pathways and biological processes associated BRCA mutations. For BRCA1/2-mutant breast cancer, wild-type breast cancer and corresponding normal tissues, three independent differentially expressed genes (DEGs) analysis were performed to validate potential hub genes with each other. Protein–protein interaction (PPI) networks, survival analysis and diagnostic value assessment helped identify key genes associated with BRCA1/2 mutations. Results The regulation process of cell cycle was significantly enriched in mutant group compared with wild-type group. A total of 294 genes were identified after analysis of DEGs between mutant patients and wild-type patients. Interestingly, by the other two comparisons, we identified 43 overlapping genes that not only significantly expressed in wild-type breast cancer patients relative to normal tissues, but more significantly expressed in BRCA1/2-mutant breast patients. Based on the STRING database and cytoscape software, we constructed a PPI network using 294 DEGs. Through topological analysis scores of the PPI network and 43 overlapping genes, we sought to select some genes, thereby using survival analysis and diagnostic value assessment to identify key genes pertaining to BRCA1/2-mutant breast cancer. CCNE1, NPBWR1, A2ML1, EXO1 and TTK displayed good prognostic/diagnostic value for breast cancer and BRCA1/2-mutant breast cancer. Conclusion Our research provides comprehensive and new insights for the identification of biomarkers connected with BRCA mutations, availing diagnosis and treatment of breast cancer and BRCA1/2-mutant breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Differentially expressed genes and key molecules of BRCA1/2-mutant breast cancer: evidence from bioinformatics analyses

Zhou

Liu

et al. 2020

PeerJ

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“…TTK, a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy (Mason et al 2017 ). Inhibition of TTK has emerged as a promising therapeutic strategy for the treatment of aneuploid tumors, with triple-negative breast cancer (TNBC) (Maia et al 2015 ; Riggs et al 2017 ; Thu et al 2018 ; Zhu et al 2018 ) and malignant mesothelioma (Szymiczek et al 2017 ) important focus of clinical development. Human cancer cells treated with Mps1 inhibitor exhibit effects consistent with Mps1 kinase inhibition, specifically spindle assembly checkpoint inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death (Mason et al 2017 ).…”

Section: The Progress Of Ttk In Immunotherapy Of Esophageal Cancermentioning

confidence: 99%

Expression of cancer–testis antigens in esophageal cancer and their progress in immunotherapy

Zhang

2019

J Cancer Res Clin Oncol

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Purpose Esophageal cancer is a common disease in China with low survival rate due to no obvious early symptoms and lack of effective screening strategies. Traditional treatments usually do not produce desirable results in patients with advanced esophageal cancer, so immunotherapy which relies on tumor-related antigens is needed to combat low survival rates effectively. Cancer-testis antigens (CTA), a large family of tumor-related antigens, have a strong in vivo immunogenicity and tumor-restricted expressing patterns in normal adult tissues. These two characteristics are ideal features of anticancer immunotherapy targets and, therefore, promoted the development of some studies of CTA-based therapy. To provide ideas for the role of the cancer-testis antigens MAGE-A, NY-ESO-1, LAGE-1, and TTK in esophageal cancer, we summarized their expression, prognostic value, and development in immunotherapy. Methods The relevant literature from PubMed is reviewed in this study. Results In esophageal cancer, although the relationship between expression of MAGE-A, NY-ESO-1, LAGE-1, and TTK and prognosis value is still in a controversial situation, MAGE-A, NY-ESO-1, LAGE-1, and TTK are highly expressed and can induce specific CTL cells to produce particular killing effect on tumor cells, and some clinical trials have demonstrated that immunotherapy for esophageal cancer patients is effective and safe, which provides a new therapeutic strategy for the treatment of esophageal cancer in the future. Conclusion In this review, we summarize expression and prognostic value of MAGE-A, NY-ESO-1, LAGE-1, and TTK in esophageal cancer and point out recent advances in immunotherapy about them.

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“…CC-671, a potent and selective inhibitor of both monopolar spindle 1 kinase, also known as TTK, and CDC like kinase 2 (CLK2), showed significant anticancer effect in a large panel of cancer cell lines. 32 The anticancer activity of CC-671 is mainly attributed to TTK inhibition. In addition, CLK2 was shown to act as an oncogene in breast cancer and inhibition of CLK2 can lead to apoptosis induction.…”

Section: Introductionmentioning

confidence: 99%

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

Yang

Wang

et al. 2020

Cancer Science

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One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR.

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The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen

Cited by 50 publications

References 33 publications

Differentially expressed genes and key molecules of BRCA1/2-mutant breast cancer: evidence from bioinformatics analyses

Differentially expressed genes and key molecules of BRCA1/2-mutant breast cancer: evidence from bioinformatics analyses

Expression of cancer–testis antigens in esophageal cancer and their progress in immunotherapy

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

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