PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1/p38(MAPK) signalling

Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults. Considering that resistance to current therapies leads to limited response in patients, new therapeutic options are urgently needed. In recent years, differentiation therapy has been proposed as an alternative for GBM treatment, with the aim of bringing cancer cells into a post-mitotic/differentiated state, ultimately limiting tumour growth. As an integral component of cancer development and regulation of differentiation processes, kinases are potential targets of differentiation therapies. The present study describes how the screening of a panel of kinase inhibitors (KIs) identified PDGF-R alpha/beta inhibitor CP-673451 as a potential differentiation agent in GBM. We show that targeting PDGF-R alpha/beta with CP-673451 in vitro triggers outgrowth of neurite-like processes in GBM cell lines and GBM stem cells (GSCs), suggesting differentiation into neural-like cells, while reducing proliferation and invasion in 3D hyaluronic acid hydrogels. In addition, we report that treatment with CP-673451 improves the anti-tumour effects of temozolomide in vivo using a subcutaneous xenograft mouse model. RNA sequencing and follow-up proteomic analysis revealed that upregulation of phosphatase DUSP1 and consecutive downregulation of phosphorylated-p38(MAPK) can underlie the pro-differentiation effect of CP-673451 on GBM cells. Overall, the present study identifies a potential novel therapeutic option that could benefit GBM patients in the future, through differentiation of residual GSCs post-surgery, with the aim to limit recurrence and improve quality of life.

Automated summary

This study identifies PDGF-R alpha/beta inhibitor CP-673451 as a potential differentiation agent for GBM. In vitro experiments showed that CP-673451 promotes differentiation of GBM cells and GBM stem cells into neural-like cells, while reducing proliferation and invasion. In vivo experiments demonstrated that CP-673451 enhances the anti-tumor effects of temozolomide. Mechanistically, upregulation of phosphatase DUSP1 and downregulation of phosphorylated-p38(MAPK) may underlie the pro-differentiation effect of CP-673451 on GBM cells.