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

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.This work was supported by grants from the Ministerio de Educación y Ciencia (MEC; SAF2008-04531), the Ministerio de Ciencia e Innovación (MICINN, PLE2009-0115), and the Ministerio de Asuntos Exteriores y Cooperación (MAEC-AECID A/023963/09; to P. Sánchez-Gómez), as well as by grants from the Fondo de Investigación Sanitaria (FIS-PS09-01977) and Fundación Mutua-madrileña grants (FMM 2007/057, to J.R. Ricoy; and FMM2011/89, to J.M. Sepúlveda).S

Impact of cardiovascular risk factors on the clinical presentation and survival of pulmonary embolism without identifiable risk factor

Background: The nature of pulmonary embolism (PE) without identifiable risk factor (IRF) remains unclear. The objective of this study is to investigate the potential relationship between cardiovascular risk factors (CVRFs) and PE without IRF (unprovoked) and assess their role as markers of disease severity and prognosis. Methods: A case-control study was performed of patients with PE admitted to our hospital [2010-2019]. Subjects with PE without IRF were included in the cohort of cases, whereas patients with PE with IRF were allocated to the control group. Variables of interest included age, active smoking, obesity, and diagnosis of arterial hypertension, dyslipidemia or diabetes mellitus. Results: A total of 1,166 patients were included in the study, of whom 64.2% had PE without IRF. The risk for PE without IRF increased with age [odds ratio (OR): 2.68; 95% confidence interval (CI): 1.95-3.68], arterial hypertension (OR: 1.63; 95% CI: 1.27-2.07), and dyslipidemia (OR: 1.63; 95% CI: 1.24-2.15). The risk for PE without IRF was higher as the number of CVRF increased, being 3.99 (95% CI: 2.02-7.90) for subjects with >/=3 CVRF. The percentage of high-risk unprovoked PE increased significantly as the number of CVRF rose [0.6% for no CVRF; 23.8% for a CRF, P/=3, P<0.001 (OR: 14.1; 95% CI: 4.06-49.4)]. No significant differences were observed in 1-month survival between cases and controls, whereas differences in 24-month survival reached significance. Conclusions: A relationship was observed between CVRF and PE without IRF, as the risk for unprovoked PE increased with the number of CVRF. In addition, the number of CVRF was associated with PE without IRF severity, but not with prognosis

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

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