Inhibition of Mesenchymal Phenotypes in Glioblastoma by Combined Targeting of NF-κB and STAT3 Pathways

Among the 3 subtypes of GBM, the mesenchymal GBM is characterized by therapeutic resistance and poor outcomes. Here, we found that both STAT3 and NF-κB pathways are abnormally activated in mesenchymal GBM and the patients with higher expression of STAT3 and NF-κB had a poor prognosis in TCGA database.

We used the STAT3 inhibitor Stattic to block STAT3 signaling in GBM cells; however, treatment with Stattic alone induced compensatory activation of the NF-κB pathway. Therefore, we hypothesized that combined inhibition of STAT3 and NF-κB pathways may has a better anti-mesenchymal GBM effect than single signaling inhibition. ACT001, a novel NF-κB inhibitor, combined with Stattic has a synergistic anti-GBM effect, effectively inhibiting GBM proliferation, invasion, migration and promoting apoptosis.