Simultaneous inhibition of discoidin domain receptor 1 and integrin αVβ3 radiosensitizes human glioblastoma cells

by Selleckchem | Jan 14 2024

Glioblastomas (GBM) are the most common primary brain tumors in adults and associated with poor clinical outcomes due to therapy resistances and destructive growth. Interactions of cancer cells with the extracellular matrix (ECM) play a pivotal role in therapy resistances and tumor progression. In this study, we investigate the functional dependencies between the discoidin domain receptor 1 (DDR1) and the integrin family of cell adhesion molecules for the radioresponse of human glioblastoma cells. By means of an RNA interference screen on DDR1 and all known integrin subunits, we identified co-targeting of DDR1/integrin β3 to most efficiently reduce clonogenicity, enhance cellular radiosensitivity and diminish repair of DNA double strand breaks (DSB). Simultaneous pharmacological inhibition of DDR1 with DDR1-IN-1 and of integrins αVβ3/αVβ5 with cilengitide resulted in confirmatory data in a panel of 2D grown glioblastoma cultures and 3D gliospheres. Mechanistically, we found that key DNA repair proteins ATM and DNA-PK are altered upon DDR1/integrin αVβ3/integrin αVβ5 inhibition, suggesting a link to DNA repair mechanisms. In sum, the radioresistance of human glioblastoma cells can effectively be declined by co-deactivation of DDR1, integrin αVβ3 and integrin αVβ5.

Comments:

This study delves into a critical area of research concerning glioblastomas, the most prevalent primary brain tumors in adults known for their resistance to treatment and aggressive growth patterns. The focus here is on understanding the interactions between cancer cells and the extracellular matrix (ECM) and how these interactions influence resistance to therapy and tumor progression.

The research specifically investigates the relationship between the discoidin domain receptor 1 (DDR1) and the integrin family of cell adhesion molecules in human glioblastoma cells' response to radiotherapy. By conducting an RNA interference screen targeting DDR1 and various integrin subunits, the study identifies that co-targeting DDR1 and integrin β3 yields the most effective reduction in clonogenicity (the ability of cells to form colonies), increased sensitivity to radiation, and decreased repair of DNA double-strand breaks (DSB).

Furthermore, the study confirms these findings by simultaneously inhibiting DDR1 with DDR1-IN-1 and integrins αVβ3/αVβ5 with cilengitide in both 2D glioblastoma cultures and 3D gliospheres. The research also suggests a mechanistic link between the inhibition of DDR1, integrins αVβ3/αVβ5, and alterations in key DNA repair proteins such as ATM and DNA-PK, implying a connection to DNA repair mechanisms.

In summary, the study proposes that human glioblastoma cells' resistance to radiotherapy can be significantly reduced by simultaneously deactivating DDR1, integrin αVβ3, and integrin αVβ5. This finding could potentially pave the way for novel therapeutic strategies aimed at enhancing the efficacy of radiotherapy in treating glioblastomas by targeting these specific molecular pathways.