+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth



Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth



Journal of Clinical Investigation 123(6): 2475-2487



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 053863651

Download citation: RISBibTeXText

PMID: 23635774

DOI: 10.1172/jci63623


Related references

EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biology 35(6): 5593-5598, 2014

Antitumor efficacy of triple monoclonal antibody inhibition of epidermal growth factor receptor (EGFR) with MM151 in EGFR-dependent and in cetuximab-resistant human colorectal cancer cells. Oncotarget 8(47): 82773-82783, 2017

Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis. Biomed Research International 2015: 315240, 2015

The role of epidermal growth factor receptor (EGFR) in male reproductive tract differentiation: stimulation of EGFR expression and inhibition of Wolffian duct differentiation with anti-EGFR antibody. Endocrinology 137(3): 905-910, 1996

Decreased EGFR expression and growth of the human derived T98G glioblastoma following treatment with antisense oligonucleotides directed against EGFR. Proceedings of the American Association for Cancer Research Annual Meeting (41): 644, 2000

Epidermal growth factor receptor (EGFR) antibody-induced antibody-dependent cellular cytotoxicity plays a prominent role in inhibiting tumorigenesis, even of tumor cells insensitive to EGFR signaling inhibition. Journal of Immunology 187(6): 3383-3390, 2011

MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC. Cancer Biology and Therapy 8(6): 522-530, 2012

MET-EGFR dimerization in lung adenocarcinoma is dependent on EGFR mtations and altered by MET kinase inhibition. Plos One 12(1): E0170798, 2017

Cancer-associated fibroblasts derived from EGFR-TKI-resistant tumors reverse EGFR pathway inhibition by EGFR-TKIs. Molecular Cancer Research 8(6): 809-820, 2011

Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Research 72(13): 3302-3311, 2012

Combined inhibition of rho-associated protein kinase and EGFR suppresses the invasive phenotype in EGFR-dependent lung cancer cells. Lung Cancer 90(2): 167-174, 2016

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR. Oncotarget 8(14): 23020-23032, 2017

Combined Inhibition of HDAC and EGFR Reduces Viability and Proliferation and Enhances STAT3 mRNA Expression in Glioblastoma Cells. Journal of Molecular Neuroscience 2019, 2019

Inhibition of EGFR activation, proliferation and tumor growth by ERRP A novel negative regulator of EGFR. Regulatory Peptides 108(1): 15, 15 August, 2002

Efficient growth inhibition of EGFR over-expressing tumor cells by an anti-EGFR nanobody. Molecular Biology Reports 40(12): 6737-6745, 2014