Simultaneous CK2/TNIK/Dyrk1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

Sato, Katsutoshi; Padgaonkar, Amol; Baker, Stacey J.; Cosenza, Stephen C.; Rechkoblit, Olga; Subbaiah, Drc Venkata; Domingo-Domènech, Josep; Port, Elisa; Reddy, M. V. Ramana; Aggarwal, Aneel K.; Irie, Hanna Y.; Reddy, Eashwer

doi:10.21203/rs.3.rs-45151/v1

Cited by 5 publications

(5 citation statements)

References 70 publications

(84 reference statements)

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“…108600 was identified in a phenotypic screen of a library of ∼4000 compounds against triple-negative breast cancer cell lines. 102 The product showed toxicity toward these cells but not toward normal cells. It appears to be a multikinase inhibitor targeting CK2α1, α2, DYRK1A, 1B, DYRK2, and TNIK (IC 50 = 50, 516, 7, 28, 5 nM, respectively).…”

Section: ■ Resultsmentioning

confidence: 96%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid “off-targets” in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

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Section: ■ Resultsmentioning

confidence: 96%

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

et al. 2023

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“…S2C , middle). TCOF1 has been shown to be phosphorylated by CK2 kinase during embryogenesis [ 34 ], and CK2 inhibitor suppresses viability of TNBC CSCs [ 35 ]. The combinatorial effects of TCOF1 knockout and CK2 inhibitor Silmitasertib were therefore being examined in our 3D TNBC model.…”

Section: Resultsmentioning

confidence: 99%

TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis

Lai

Huang

et al. 2021

Br J Cancer

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Background Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Our data also revealed TCOF1 as a putative TNBC-specific super-enhancer-regulated gene. TCOF1 plays a critical role in craniofacial development but its function in cancer remains unclear. Methods Overall survival and multivariant Cox regression analyses were conducted using the METABRIC data set. The effect of TCOF1 knockout on TNBC growth and stemness was evaluated by in vitro and in vivo assays. RNA-seq and rescue experiments were performed to explore the underlying mechanisms. Results TCOF1 is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. TCOF1 depletion significantly inhibits the growth and stemness of basal-like TNBC, but not of mesenchymal-like cells, highlighting the distinct molecular dependency in different TNBC subgroups. RNA-seq uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that KIT is a downstream effector of TCOF1 in mediating TNBC stemness. TCOF1 expression in TNBC is regulated by the predicted super-enhancer. Conclusions TCOF1 depletion potently attenuates the growth and stemness of basal-like TNBC. Expression of TCOF1 may serve as a TNBC prognostic marker and a therapeutic target.

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“…BC is the most universal cancer that endangers women's lives today [1]. TNBC is a subtype of BC with negative estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) [2], account-ing for 15-20% of all diagnosed BC, and has the characteristics of strong invasiveness, rapid distant metastasis, and short survival time [3].…”

Section: Introductionmentioning

confidence: 99%

HSPA8 Is a New Biomarker of Triple Negative Breast Cancer Related to Prognosis and Immune Infiltration

Ying

Nie

et al. 2022

Disease Markers

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Objective. Triple negative breast cancer (TNBC) is a kind of cancer that endangers the lives of women all over the world in the 21st century. Heat shock protein member 8 (HSPA8) is the chaperone gene of the heat shock protein family. It is involved in many cellular functions. For example, it promotes the circulation between ATP and ADP, participates in protein folding, and can change the vitality of the cell and inhibit its growth. However, the abnormal expression of HSPA8 gene in TNBC and its diagnostic and prognostic significance still need to be further studied. Methods. First, we used related databases (such as TCGA, GEO, GTEx, ONCOMINE, TIMER2.0, UALCAN, HPA, STRING, CCLE, and Kaplan-Meier plotter databases) to analyze the relationship between HSPA8 and TNBC by bioinformatics. Then, the analysis using only a small part of the experimental work is used to explain our findings. For example, HSPA8 protein expression was evaluated by immunohistochemical method in TNBC tissues. Western blotting experiments were carried out to verify the results. Then, the clinicopathological characteristics of patients with TNBC were analyzed by R software and Cox regression analysis. On the basis, a nomogram is constructed to estimate the 1-, 3-, and 5-year overall survival (OS). The prognostic nomogram performance was calibrated and evaluated by the calibration curve and receiver operating characteristic (ROC) curve. Results. In the study, we analyzed the three GEO databases (including GSE86945, GSE106977, and GSE102088) and found that HSPA8 is one of the central genes of TNBC. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) researches indicated that HSPA8 was mainly involved in partner-mediated autophagy, mRNA catabolism, neutrophil activation, immune response, protein targeting, RNA splicing, RNA catabolism, and other biological processes. Next, we used bioinformatics technology to find that the expression level of HSPA8 in breast cancer (BC) and TNBC samples was significantly higher than that in normal breast tissues, which was determined by analyzing hospital patient samples and related experiments. In addition, the expression level of HSPA8 in BC and TNBC samples was significantly correlated with clinical indexes such as TNM stage. The Cox analysis revealed that the expression of HSPA8 in TNBC had significant clinical prognostic value. The results of nomogram and ROC test show that HSPA8 has significant predictive ability in TNBC. The results of immune infiltration of HSPA8 through the TIMER2.0 database showed that there was a significant correlation between HSPA8 and immune cell subsets. Conclusions. Our results show that the expression of HSPA8 in TNBC has important clinical diagnostic significance and clarify the potential molecular mechanism that promotes the evolution of TNBC. The high expression of HSPA8 may be related with the poor clinical outcome of TNBC. This helps to provide us with a new direction of TNBC targeted therapy.

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Simultaneous CK2/TNIK/Dyrk1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease

Cited by 5 publications

References 70 publications

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis

HSPA8 Is a New Biomarker of Triple Negative Breast Cancer Related to Prognosis and Immune Infiltration

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