title: Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth.
abstract: 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.
authors: Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain.
authors: Natividad
authors: N
authors: Pozo
authors: Cristina
authors: C
authors: Zahonero
authors: Paloma
authors: P
authors: Fernández
authors: Jose M
authors: JM
authors: Liñares
authors: Angel
authors: A
authors: Ayuso
authors: Masatoshi
authors: M
authors: Hagiwara
authors: Angel
authors: A
authors: Pérez
authors: Jose R
authors: JR
authors: Ricoy
authors: Aurelio
authors: A
authors: Hernández-Laín
authors: Juan M
authors: JM
authors: Sepúlveda
authors: Pilar
authors: P
authors: Sánchez-Gómez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006247:Harmine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000473:pathology; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D000097603:Dyrk Kinases
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D006247:Harmine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000097603:Dyrk Kinases
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