Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor–initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation–regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.
Natividad Pozo, Cristina Zahonero, Paloma Fernández, Jose M. Liñares, Angel Ayuso, Masatoshi Hagiwara, Angel Pérez, Jose R. Ricoy, Aurelio Hernández-Laín, Juan M. Sepúlveda, Pilar Sánchez-Gómez
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Molecular roles in membrane receptor signaling pathways and cascade reactions in chondrocytes: a review.
Zhu Y, Zhu J, Wang X, Wang P, Liu R |
Journal of molecular histology | 2025 |
Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis fungoides
Bordeaux ZA, Reddy SV, Choi J, Braun G, McKeel J, Lu W, Yossef SM, Ma EZ, West CE, Kwatra SG, Kwatra MM |
Scientific Reports | 2024 |
Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer
Sadat Kalaki N, Ahmadzadeh M, Najafi M, Mobasheri M, Ajdarkosh H, Karbalaie Niya MH |
Biochemistry and Biophysics Reports | 2024 |
Targeting the DYRK1A kinase prevents cancer progression and metastasis and promotes cancer cells response to G1/S targeting chemotherapy drugs
Laham AJ, El-Awady R, Ayad MS, Wang N, Yan G, Boudreault J, Ali S, Lebrun JJ |
npj Precision Oncology | 2024 |
N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents
Mostafa N, Chen PJ, Darwish SS, Su YC, Shiao MH, Piazza GA, Abadi AH, Engel M, Abdel-Halim M |
Cancers | 2024 |
Human Cytomegalovirus Dysregulates Cellular Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases and Sonic Hedgehog Pathway Proteins in Neural Astrocyte and Placental Models
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Viruses | 2024 |
Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer
Carey-Smith SL, Kotecha RS, Cheung LC, Malinge S |
International journal of molecular sciences | 2024 |
DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity
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eLife | 2024 |
Design, synthesis, and structure–activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors
Faouzi A, Arnaud A, Hallé F, Roussel J, Aymard M, Denavit V, Do CV, Mularoni A, Salah M, ElHady A, Pham TN, Bancet A, Le Borgne M, Terreux R, Barret R, Engel M, Lomberget T |
RSC Medicinal Chemistry | 2024 |
Topical GZ21T Inhibits the Growth of Actinic Keratoses in a UVB-Induced Model of Skin Carcinogenesis
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2023 | |
DYRK1A-mediated PLK2 phosphorylation regulates the proliferation and invasion of glioblastoma cells
Tan S, Zhao J, Wang P |
International journal of oncology | 2023 |
Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A
Ananthapadmanabhan V, Shows KH, Dickinson AJ, Litovchick L |
Frontiers in Cell and Developmental Biology | 2023 |
Truncated Dyrk1A aggravates neuronal apoptosis by inhibiting ASF-mediated Bcl-x exon 2b inclusion.
Zhang S, Zhong J, Xu L, Wu Y, Xu J, Shi J, Gu Z, Li X, Jin N |
CNS Neuroscience & Therapeutics | 2023 |
Harmine reinforces the effects of regorafenib on suppressing cell proliferation and inducing apoptosis in liver cancer cells
Z Chen, J Li, S Zhu, Z Li, J Yu, J Wu, C Zhang, L Zeng |
Experimental and therapeutic medicine | 2022 |
IDP-410: a Novel Therapeutic Peptide that Alters N-MYC Stability and Reduces Angiogenesis and Tumor Progression in Glioblastomas
R Gargini, B Segura-Collar, M Garranzo-Asensio, R Hortigüela, P Iglesias-Hernández, D Lobato-Alonso, M Moreno-Raja, S Esteban-Martin, J Sepúlveda-Sánchez, L Nevola, P Sánchez-Gómez |
Neurotherapeutics | 2022 |
The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target
M Rammohan, E Harris, R Bhansali, E Zhao, L Li, J Crispino |
Oncogene | 2022 |
Selective Macrocyclic Inhibitors of DYRK1A/B
C Powell, J Hatcher, J Jiang, P Vatsan, J Che, N Gray |
ACS Medicinal Chemistry Letters | 2022 |
GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma
J Choi, Z Bordeaux, J McKeel, C Nanni, N Sutaria, G Braun, C Davis, M Miller, M Alphonse, S Kwatra, C West, M Kwatra |
International journal of molecular sciences | 2022 |
A Bioinformatics Evaluation of the Role of Dual-Specificity Tyrosine-Regulated Kinases in Colorectal Cancer
A Laham, R El-Awady, J Lebrun, M Ayad |
Cancers | 2022 |
Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction
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EBioMedicine | 2022 |
A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness
Antonica F, Santomaso L, Pernici D, Petrucci L, Aiello G, Cutarelli A, Conti L, Romanel A, Miele E, Tebaldi T, Tiberi L |
Nature Communications | 2022 |
The Omnipresence of DYRK1A in Human Diseases
Deboever E, Fistrovich A, Hulme C, Dunckley T |
International journal of molecular sciences | 2022 |
Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System
Huizar FJ, Hill HM, Bacher EP, Eckert KE, Gulotty EM, Rodriguez KX, Tucker ZD, Banerjee M, Wiest O, Zartman J, Ashfeld BL |
ChemMedChem | 2022 |
DYRK1A regulates B-cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3
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Journal of Clinical Investigation | 2021 |
Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells
A Recasens, SJ Humphrey, M Ellis, M Hoque, RH Abbassi, B Chen, M Longworth, EJ Needham, DE James, TG Johns, BW Day, M Kassiou, P Yang, L Munoz |
Cell Death Discovery | 2021 |
C3G downregulation induces the acquisition of a mesenchymal phenotype that enhances aggressiveness of glioblastoma cells
S Manzano, A Gutierrez-Uzquiza, P Bragado, C Sequera, Ó Herranz, M Rodrigo-Faus, P Jauregui, S Morgner, I Rubio, C Guerrero, A Porras |
Cell Death and Disease | 2021 |
DYRK1A phosphorylates MEF2D and decreases its transcriptional activity
P Wang, J Zhao, X Sun |
Journal of Cellular and Molecular Medicine | 2021 |
Diabetic Kinome Inhibitors—A New Opportunity for β-Cells Restoration
B Pucelik, A Barzowska, JM Dąbrowski, A Czarna |
International journal of molecular sciences | 2021 |
Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview
MF Lindberg, L Meijer |
International journal of molecular sciences | 2021 |
K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR
P Zhang, Z Zhang, Y Fu, Y Zhang, MP Washburn, L Florens, M Wu, C Huang, Z Hou, M Mohan |
Cell Death and Disease | 2021 |
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Y Chen, X Shao, J Cao, H Zhu, B Yang, Q He, M Ying |
Acta pharmaceutica Sinica. B | 2021 |
Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma
AJ Massey, K Benwell, M Burbridge, A Kotschy, DL Walmsley |
Journal of Cellular and Molecular Medicine | 2021 |
Identification of harmine and β-carboline analogs from a high-throughput screen of an approved drug collection; profiling as differential inhibitors of DYRK1A and monoamine oxidase A and for in vitro and in vivo anti-cancer studies
M Tarpley, HO Oladapo, D Strepay, TB Caligan, L Chdid, H Shehata, JR Roques, R Thomas, CP Laudeman, RU Onyenwoke, DB Darr, KP Williams |
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | 2021 |
TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression
L Li, JR Wei, Y Song, S Fang, Y Du, Z Li, TT Zeng, YH Zhu, Y Li, XY Guan |
Cell Death and Disease | 2021 |
Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome
W Stensen, U Rothweiler, RA Engh, MR Stasko, I Bederman, AC Costa, A Fugelli, JS Svendsen |
Pharmaceuticals (Basel, Switzerland) | 2021 |
The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities
J Boni, C Rubio-Perez, N López-Bigas, C Fillat, S de la Luna |
Cancers | 2020 |
DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis
AJ Laham, M Saber-Ayad, R El-Awady |
Cellular and Molecular Life Sciences | 2020 |
A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay
KS Lee, M Choi, DW Kwon, D Kim, JM Choi, AK Kim, Y Ham, SB Han, S Cho, CK Cheon |
Scientific Reports | 2020 |
The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas
R Gargini, B Segura-Collar, B Herránz, V García-Escudero, A Romero-Bravo, FJ Núñez, D García-Pérez, J Gutiérrez-Guamán, A Ayuso-Sacido, J Seoane, A Pérez-Núñez, JM Sepúlveda-Sánchez, A Hernández-Laín, MG Castro, R García-Escudero, J Ávila, P Sánchez-Gómez |
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N Kokkorakis, M Gaitanou |
World journal of stem cells | 2020 |
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Midkine signaling maintains the self-renewal and tumorigenic capacity of glioma initiating cells
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A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response
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G Pallavicini, GE Berto, FD Cunto |
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Ocoxin Modulates Cancer Stem Cells and M2 Macrophage Polarization in Glioblastoma
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Oxidative medicine and cellular longevity | 2019 |
DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild‐type NSCLC cells to AZD9291
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Journal of Cellular and Molecular Medicine | 2019 |
[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors
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Scientific Reports | 2018 |
DYRK1A interacts with histone acetyl transferase p300 and CBP and localizes to enhancers
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Novel selective thiadiazine DYRK1A inhibitor lead scaffold with human pancreatic β-cell proliferation activity
K Kumar, PM Ung, P Wang, H Wang, H Li, MK Andrews, AF Stewart, A Schlessinger, RJ DeVita |
European Journal of Medicinal Chemistry | 2018 |
Harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor induces caspase-mediated apoptosis in neuroblastoma
KL Uhl, CR Schultz, D Geerts, AS Bachmann |
Cancer Cell International | 2018 |
A facile consensus ranking approach enhances virtual screening robustness and identifies a cell-active DYRK1α inhibitor
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Future Medicinal Chemistry | 2018 |
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Plant physiology | 2018 |
A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis
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ODZ1 allows glioblastoma to sustain invasiveness through a Myc-dependent transcriptional upregulation of RhoA
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A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma
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Scientific Reports | 2016 |
DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3
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Journal of Experimental Medicine | 2015 |
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Molecular and Cellular Biochemistry | 2015 |
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W Sawadogo, R Boly, C Cerella, M Teiten, M Dicato, M Diederich |
Molecules (Basel, Switzerland) | 2015 |
DYRK1A Controls HIV-1 Replication at a Transcriptional Level in an NFAT Dependent Manner
T Booiman, VV Loukachov, KA van Dort, AB van Wout, NA Kootstra, A Marcello |
PloS one | 2015 |
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González-Gómez P, Crecente-Campo J, Zahonero C, de la Fuente M, Hernández-Laín A, Mira H, Sánchez-Gómez P, Garcia-Fuentes M |
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P Fernández-Martínez, C Zahonero, P Sánchez-Gómez |
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C Zahonero, P Sánchez-Gómez |
Cellular and Molecular Life Sciences | 2014 |
Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis
I Vyazunova, VI Maklakova, S Berman, I De, MD Steffen, W Hong, H Lincoln, AS Morrissy, MD Taylor, K Akagi, CW Brennan, FJ Rodriguez, LS Collier, AC Wilber |
PloS one | 2014 |