Enhancing therapy sensitivity is a big challenge in oncology. Based on genetic and epigenetic modifications altering intra- and extracellular processes, glioblastoma (GBM) belongs to the group of tumor entities with unmet need, is highly refractory to therapy and associated with poor clinical outcome. Novel effective treatment approaches are urgently required. Here, we found the collagen type-I receptors discoidin domain receptor 1 (DDR1) and beta1 integrin overexpressed in GBM. We identified a critical function of the promitotic and adhesion-mediating DDR1 in altering GBM treatment resistance. In a large number of GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We exhibit DDR1 inhibition in combination with radiochemotherapy using temozolomide in GBM models to enhance sensitivity and prolong survival to a degree superior to conventional therapy. We further identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1. This protein complex is required for prosurvival Akt and mTOR signaling and the regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance via autophagy and suggest DDR1 as a rationale target for the development of therapy-sensitizing agents.
Dr. Nils Cordes graduated from Medical School of the University Erlangen-Nürnberg, Germany, in 1998. Subsequently, he worked as resident in radiation oncology at the Universities Erlangen-Nürnberg and Tübingen before he took on a position as radiobiologist at the Institute of Radiobiology of the German Army. His studies on cell-matrix interactions pioneered the field by untangling the role of the cancer cell adhesion resistome. In 2010, he became Full Professor of Radiobiology at the Technische Universität Dresden, and Head of Radiobiology of OncoRay and the Department of Radiobiology, Institute of Radiooncology, Helmholtz Center Dresden-Rossendorf. Based on Dr. Cordes´ research, our understanding of how cancer cells resist therapy by adhesion to extracellular matrix or neighboring cells has essentially increased. By using more physiological, matrix-based 3D cell cultures, it become obvious that the physiological environment mediates a tremendous impact on signal transduction, gene expression, chromatin organization and adaptation mechanisms induced by therapy.