DSTYK

Last update 08 May 2025

Basic Info

Synonyms

DSTYK, Dual serine/threonine and tyrosine protein kinase, Dusty PK

+ [12]

Introduction

Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation (PubMed:23862974, PubMed:28157540). Involved in the regulation of both caspase-dependent apoptosis and caspase-independent cell death (PubMed:15178406). In the skin, it plays a predominant role in suppressing caspase-dependent apoptosis in response to UV stress in a range of dermal cell types (PubMed:28157540).

100 Clinical Results associated with DSTYK

100 Translational Medicine associated with DSTYK

0 Patents (Medical) associated with DSTYK

Literatures (Medical) associated with DSTYK

01 Mar 2025·Journal of Thoracic Oncology

DSTYK Inhibition Sensitizes NSCLC to Taxane-Based Chemotherapy

Article

Author: Montuenga, Luis M. ; Fernández-Irigoyen, Joaquín ; Provencio, Mariano ; Zandueta, Carolina ; Cruz-Bermúdez, Alberto ; Arricibita, Andrea ; Santamaría, Enrique ; Valencia, Karmele ; Echepare, Mirari ; Gentili, Marco ; Pasquier, Andrea ; Roz, Luca ; Facchinetti, Federica ; Teijeira, Álvaro ; Picabea, Beñat ; Montuenga, Luis M ; Sanchez-Cespedes, Montse ; Otegui, Nerea ; Lecanda, Fernando ; Hernández, Javier ; Romero, Octavio ; Felip, Enriqueta

INTRODUCTIONChemotherapy continues to be the standard treatment for patients noneligible for targeted or immune-based therapies; nevertheless, treatment resistance remains a major clinical challenge. We previously found that expression levels of DSTYK, a poorly explored dual serine/threonine and tyrosine kinase frequently amplified in cancer, identified patients with lung cancer exhibiting poor response to immune checkpoint inhibitors, and found that its inhibition sensitizes to immunotherapy. Seeking to explore the potential of DSTYK targeting in additional indications, we investigated the functional relevance and actionability of DSTYK in lung cancer chemoresistance.METHODSIn silico analysis to study the differential sensitivity to paclitaxel, carboplatin, pemetrexed, and cisplatin drugs was performed using pan-cancer human cancer cell line DSTYK CN data downloaded from Depmap portal (https://depmap.org/portal/depmap/). Two cohorts of patients with lung cancer were used. An adjuvant cohort composed of patients with advanced IV-stage lung adenocarcinoma treated with carboplatin plus paclitaxel or carboplatin plus pemetrexed in the first line from VHIO; A neoadjuvant cohort including resectable stage IIIA or IIIB NSCLC tumor samples of patients from NADIM I and NADIM II clinical trials perioperative treated with nivolumab plus chemotherapy (carboplatin + paclitaxel). DSTYK CN was assessed by fluorescence in situ hybridization and quantitative reverse transcription-polymerase chain reaction. Proteomics and bioinformatic analyses were performed to study differentially expressed protein signatures. Functional in vitro experiments (adhesion, migration, and invasion) in both murine and human systems, and in vivo lung orthotopic, intracardiac, and intratibial xenograft and syngeneic models complete the study.RESULTSWe show that DSTYK depletion specifically sensitizes lung cancer cells to taxane-based chemotherapy, particularly in combination with carboplatin. Mechanistically, DSTYK ablation remodels the cytoskeleton and impairs distant invasion and metastatic outgrowth in vivo. DSTYK downregulation sensitizes both primary and metastatic lung tumors to chemoimmunotherapy treatment leading to tumor regression in mouse models. Consistently, clinical data of patients with early and advanced lung cancer-in the neoadjuvant and adjuvant settings-show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making.CONCLUSIONSCollectively, our data indicates that DSTYK amplification may be a predictor of resistance to taxane-based treatments and represents an actionable target for these patients.

01 Oct 2024·Computers in Biology and Medicine

Genetic analysis from multiple cohorts implies causality between 2200 druggable genes, telomere length, and leukemia

Article

Author: Du, Xiaofeng ; Lv, Liyuan ; Zhao, Hongbin ; Liu, Zhu ; Yun, Zhangjun ; Zhang, Yayue ; Hou, Li ; Sun, Ziyi ; Shen, Yang

BACKGROUNDClinical therapeutic targets for leukemia remain to be identified and the causality between leukemia and telomere length is unclear.METHODSThis work employed cis expression quantitative trait locus (eQTL) for 2,200 druggable genes from the eQTLGen Consortium and genome-wide association studies (GWAS) summary data for telomere length in seven blood cell types from the UK Biobank, Netherlands Cohort as exposures. GWAS data for lymphoid leukemia (LL) and myeloid leukemia (ML) from FinnGen and Lee Lab were used as outcomes for discovery and replication cohorts, respectively. Robust Mendelian randomization (MR) findings were generated from seven MR models and a series of sensitivity analyses. Summary-data-based MR (SMR) analysis and transcriptome-wide association studies (TWAS) were further implemented to verify the association between identified druggable genes and leukemia. Single-cell type expression analysis was employed to identify the specific expression of leukemia casual genes on human bone marrow and peripheral blood immune cells. Multivariable MR analysis, linkage disequilibrium score regression (LDSC), and Bayesian colocalization analysis were performed to further validate the relationship between telomere length and leukemia. Mediation analysis was used to assess the effects of identified druggable genes affecting leukemia via telomere length. Phenome-wide MR (Phe-MR) analysis for assessing the effect of leukemia causal genes and telomere length on 1,403 disease phenotypes.RESULTSCombining the results of the meta-analysis for MR estimates from two cohorts, SMR and TWAS analysis, we identified five LL causal genes (TYMP, DSTYK, PPIF, GDF15, FAM20A) and three ML causal genes (LY75, ADA, ABCA2) as promising drug targets for leukemia. Univariable MR analysis showed genetically predicted higher leukocyte telomere length increased the risk of LL (odds ratio [OR] = 2.33, 95 % confidence interval [95 % CI] 1.70-3.18; P = 1.33E-07), and there was no heterogeneity and horizontal pleiotropy. Evidence from the meta-analysis of two cohorts strengthened this finding (OR = 1.88, 95 % CI 1.06-3.05; P = 0.01). Multivariable MR analysis showed the causality between leukocyte telomere length and LL without interference from the other six blood cell telomere length (OR = 2.72, 95 % CI 1.88-3.93; P = 1.23E-07). Evidence from LDSC supported the positive genetic correlation between leukocyte telomere length and LL (r_g = 0.309, P = 0.0001). Colocalization analysis revealed that the causality from leukocyte telomere length on LL was driven by the genetic variant rs770526 in the TERT region. The mediation analysis via two-step MR showed that the causal effect from TYMP on LL was partly mediated by leukocyte telomere length, with a mediated proportion of 12 %.CONCLUSIONOur study identified several druggable genes associated with leukemia risk and provided new insights into the etiology and drug development of leukemia. We also found that genetically predicted higher leukocyte telomere length increased LL risk and its potential mechanism of action.

01 Sep 2024·Molecular Neurobiology

Ripks and Neuroinflammation

Review

Author: Xu, Yue ; Zhang, Lei ; Chen, Wenli ; Lin, Feng ; Liao, Guolei ; Sun, Jiaxing

Neuroinflammation is an immune response in the central nervous system and poses a significant threat to human health. Studies have shown that the receptor serine/threonine protein kinase family (RIPK) family, a popular research target in inflammation, has been shown to play an essential role in neuroinflammation. It is significant to note that the previous reviews have only examined the link between RIPK1 and neuroinflammation. However, it has yet to systematically analyze the relationship between the RIPK family and neuroinflammation. Activation of RIPK1 promotes neuroinflammation. RIPK1 and RIPK3 are responsible for the control of cell death, including apoptosis, necrosis, and inflammation. RIPK1 and RIPK3 regulate inflammatory responses through the release of damage in necroptosis. RIPK1 and RIPK3 regulate inflammatory responses by releasing damage-associated molecular patterns (DAMPs) during necrosis. In addition, activated RIPK1 nuclear translocation and its interaction with the BAF complex leads to upregulation of chromatin modification and inflammatory gene expression, thereby triggering inflammation. Although RIPK2 is not directly involved in regulating cell death, it is considered an essential target for treating neurological inflammation. When the peptidoglycan receptor detects peptidoglycan IE-DAP or MDP in bacteria, it prompts NOD1 and NOD2 to recruit RIPK2 and activate the XIAP E3 ligase. This leads to the K63 ubiquitination of RIPK2. This is followed by LUBAC-mediated linear ubiquitination, which activates NF-KB and MAPK pathways to produce cytokines and chemokines. In conclusion, there are seven known members of the RIPK family, but RIPK4, RIPK5, RIPK6, and RIPK7 have not been linked to neuroinflammation. This article seeks to explore the potential of RIPK1, RIPK2, and RIPK3 kinases as therapeutic interventions for neuroinflammation, which is associated with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ischemic stroke, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI).

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