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Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy

Anne Vehlow1, Erik Klapproth2, Sha Jin3

  • 1OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden Rossendorf, Dresden 01307, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg 69192, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz Association/Helmholtz-Zentrum Dresden Rossendorf (HZDR), Dresden 01307, Germany.

Cell Reports
|March 28, 2019
PubMed

Insights

Discoidin domain receptor 1 (DDR1) drives glioblastoma therapy resistance by regulating autophagy and prosurvival signaling. Inhibiting DDR1 enhances treatment effectiveness and survival in glioblastoma models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis.
  • Therapy resistance is a major challenge in treating GBM patients.

Purpose of the Study:

  • To investigate the role of discoidin domain receptor 1 (DDR1) in GBM therapy resistance.
  • To identify mechanisms by which DDR1 influences GBM treatment outcomes.

Main Methods:

  • Analysis of DDR1 and GBM stem cell marker co-expression in GBM samples.
  • Inhibition of DDR1 in combination with radiochemotherapy and temozolomide in GBM models.
  • Identification of protein complexes involving DDR1 using biochemical assays.

Main Results:

  • DDR1 co-expression with GBM stem cell markers correlates with patient outcomes.
  • DDR1 inhibition combined with standard therapy improved GBM model sensitivity and survival.
  • A DDR1-associated protein complex (14-3-3-Beclin-1-Akt1) was identified, regulating Akt/mTOR signaling and autophagy.

Conclusions:

  • DDR1 plays a critical role in GBM therapy resistance.
  • Targeting DDR1 offers a potential strategy to sensitize GBM to existing therapies.
  • The DDR1-mediated signaling pathway presents a novel therapeutic target for improving GBM treatment.
Keywords:
14-3-3Akt1Beclin-1GBM stem-like cellsautophagydiscoidin domain receptor 1glioblastomamTORorthotopic GBM mouse modelradiochemotherapytherapy resistance

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