scholarly journals The Clinical Kinase Index: Prioritizing Understudied Kinases as Targets for the Treatment of Cancer

2020 ◽  
Author(s):  
Derek Essegian ◽  
Rimpi Khurana ◽  
Vasileios Stathias ◽  
Stephan C. Schürer
Keyword(s):  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
The Cancer Genome Atlas ◽  
Clinical Value ◽  
Target Class ◽  
Hotspot Analysis ◽  
Oncological Treatment ◽  
Cancer Genome Atlas ◽  
Differential Gene

AbstractThe approval of the first kinase inhibitor, Gleevec, in 2001, ushered in a paradigm shift for oncological treatment—the use of genomic data for targeted, efficacious therapies. Since then, over 48 additional small molecule kinase inhibitors have been approved, solidifying the case for kinases as a highly druggable and attractive target class. Despite the established role deregulated kinase activity plays in cancer, only 8% of the entire kinome has been effectively “drugged”. Moreover, a quarter of the 634 human kinases are vastly understudied. We have developed a comprehensive scoring system which utilizes differential gene expression, clinical and pathological parameters, overall survival and mutational hotspot analysis to rank and prioritize clinically-relevant kinase targets across 17 solid tumor cancers from The Cancer Genome Atlas (TCGA). Collectively, we report that dark kinases have potential clinical value as biomarkers or as new drug targets that warrant further study.

scholarly journals Exploring the understudied human kinome for research and therapeutic opportunities

2020 ◽  
Author(s):  
Nienke Moret ◽  
Changchang Liu ◽  
Benjamin M. Gyori ◽  
John A. Bachman ◽  
Albert Steppi ◽  
...  
Keyword(s):  
Drug Targets ◽  
Kinase Inhibitors ◽  
The Cancer Genome Atlas ◽  
Public Knowledge ◽  
Substantial Fraction ◽  
The Public ◽  
Cancer Genome Atlas ◽  
Automatic Reading ◽  
Human Kinome ◽  
Genome Atlas

ABSTRACTThe functions of protein kinases have been widely studied and many kinase inhibitors have been developed into FDA-approved therapeutics. A substantial fraction of the human kinome is nonetheless understudied. In this perspective, members of the NIH Understudied Kinome Consortium mine publicly available databases to assess the functionality of these understudied kinases as well as their potential to be therapeutic targets for drug discovery campaigns. We start with a re-analysis of the kinome as a whole and describe criteria for creating an inclusive set of 710 kinase domains as well as a curated set of 557 protein kinase like (PKL) domains. We define an understudied (‘dark’) kinome by quantifying the public knowledge on each kinase with a PKL domain using an automatic reading machine. We find a substantial number are essential in the Cancer Dependency Map and differentially expressed or mutated in disease databases such as The Cancer Genome Atlas. Based on this and other data, it seems likely that the dark kinome contains biologically important genes, a subset of which may be viable drug targets.

scholarly journals Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

scholarly journals PABPC1 relevant bioinformatic profiling and prognostic value in gliomas

2020 ◽  
Vol 16 (1) ◽  
pp. 4279-4288 ◽  
Author(s):  
Qiangwei Wang ◽  
Zhiliang Wang ◽  
Zhaoshi Bao ◽  
Chuanbao Zhang ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Biological Process ◽  
The Cancer Genome Atlas ◽  
Analysis Tool ◽  
Expression Data ◽  
Clinical Value ◽  
Mrna Expression Data ◽  
R Language ◽  
Molecular Features ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Aim: We aimed at investigating molecular features and potential clinical value of PABPC1 in gliomas. Materials & methods: We assembled totally 1000 glioma samples with mRNA expression data from Chinese Glioma Genome Atlas and The Cancer Genome Atlas. We utilized R language as the main analysis tool. Gene Ontology was performed for functional analysis. Results: PABPC1 was downregulated in gliomas with higher malignance and PABPC1 may contribute as potential predictor of proneural subtype in gliomas. Higher expression of PABPC1 was significantly related to better prognosis and related to biological process of translation. Conclusion: Our finding improves the understanding of PABPC1 as a novel biomarker with potential therapeutic connotations.

Nicht kleinzelliges Lungenkarzinom: Welche Rolle microRNA in der Behandlung spielt

2019 ◽  
Vol 7 (6) ◽  
pp. 318-319
Author(s):  
Niels Reinmuth
Keyword(s):  
Meta Analysis ◽  
The Cancer Genome Atlas ◽  
High Expression ◽  
Kleinzelliges Lungenkarzinom ◽  
Clinical Value ◽  
Lung Cancers ◽  
Cancer Genome Atlas ◽  
Clinicopathologic Parameters ◽  
Nsclc Patients

Background: The role of microRNA-133a (miR-133a) in non-small cell lung cancers (NSCLCs) is controversial. Thus, we conducted a comprehensive study based on meta-analysis and The Cancer Genome Atlas (TCGA) database. Methods: Publications were searched in both English and Chinese databases, and meta-analysis was performed using Stata 12.0. The clinical value of miR-133a in NSCLC was investigated by collecting and calculating data from the TCGA database, and the statistical analysis was performed in R 3.5.0. Results: 5 studies with 364 cases were included in this meta-analysis. The combined pooled result showed that high expression of miR-133a was associated with a favorable survival outcome in NSCLC patients (hazard ratio 0.561, 95% confidence interval 0.396-0.794, p = 0.001). Meanwhile, a total of 984 NSCLC patients were extracted from the TCGA database. Results showed an area under the ROC curve value for miR-133a-3p of 0.902, and the expression of miR-133a-3p was linked with clinicopathologic parameters of NSCLC (p < 0.05), including sex, age, social status, and lymph node metastasis. Conclusion: Our study indicated that miR-133a might act as a tumor suppressor and be a valuable independent prognostic and diagnostic biomarker for NSCLC, and NSCLC patients with high expression of miR-133 might have a better prognosis.

scholarly journals Oxidative Stress—Part of the Solution or Part of the Problem in the Hypoxic Environment of a Brain Tumor

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 747 ◽  
Author(s):  
Kamil Krawczynski ◽  
Jakub Godlewski ◽  
Agnieszka Bronisz
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Reactive Oxygen ◽  
The Cancer Genome Atlas ◽  
Oxygen Species ◽  
Hypoxic Environment ◽  
Metadata Analysis ◽  
Cancer Genome Atlas ◽  
Differential Gene

Rapid growth of brain tumors such as glioblastoma often results in oxygen deprivation and the emergence of hypoxic zones. In consequence, the enrichment of reactive oxygen species occurs, harming nonmalignant cells and leading them toward apoptotic cell death. However, cancer cells survive such exposure and thrive in a hypoxic environment. As the mechanisms responsible for such starkly different outcomes are not sufficiently explained, we aimed to explore what transcriptome rearrangements are used by glioblastoma cells in hypoxic areas. Using metadata analysis of transcriptome in different subregions of the glioblastoma retrieved from the Ivy Glioblastoma Atlas Project, we created the reactive oxygen species-dependent map of the transcriptome. This map was then used for the analysis of differential gene expression in the histologically determined cellular tumors and hypoxic zones. The gene ontology analysis cross-referenced with the clinical data from The Cancer Genome Atlas revealed that the metabolic shift is one of the major prosurvival strategies applied by cancer cells to overcome hypoxia-related cytotoxicity.

scholarly journals Development of an Antivirulence Drug againstStreptococcus mutans: Repression of Biofilm Formation, Acid Tolerance, and Competence by a Histidine Kinase Inhibitor, Walkmycin C

2011 ◽  
Vol 55 (4) ◽  
pp. 1475-1484 ◽  
Author(s):  
Yoko Eguchi ◽  
Norihiro Kubo ◽  
Hiroko Matsunaga ◽  
Masayuki Igarashi ◽  
Ryutaro Utsumi
Keyword(s):  
Histidine Kinase ◽  
Biofilm Formation ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Acid Tolerance ◽  
Gene Clusters ◽  
Pathogenic Potential ◽  
Acid Sensitivity

ABSTRACTTwo-component signal transduction systems (TCSs) in prokaryotes often regulate gene clusters that induce pathogenicity, and thus they have frequently been proposed as potential drug targets for attenuating the virulence of pathogens. The pathogenic potential ofStreptococcus mutans, the major etiological pathogen of dental caries, is also regulated by its TCSs. The object of this study was to evaluate the effect of a histidine kinase (HK) inhibitor against two major virulence factors ofS. mutans: biofilm formation and acid tolerance. Walkmycin C (WKM C), an HK inhibitor isolated from the screening of inhibitors against WalK HK inBacillus subtilis, inhibited thein vitroautophosphorylation activity of three purifiedS. mutansHKs, i.e., VicK, CiaH, and LiaS. AlthoughS. mutansdoes not have any essential HK but only an essential response regulator, VicR, WKM C showed an MIC of 6.25 μg/ml. This inhibitory effect of WKM C suggests that blocking the autophosphorylation of multiple HKs may inhibit phosphotransfer to VicR from VicK and other HKs. When WKM C was added at sub-MIC levels, the cells formed abnormal biofilms and also showed a defect in competence. When the cells were pretreated with WKM C, an increase in acid sensitivity was observed. Our results show that WKM C represses two pathogenic phenotypes ofS. mutans, indicating the possibility of developing histidine kinase inhibitors into antivirulence drugs.

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