Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo

Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy, patient's survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed an immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy. •We develop an integrated syngeneic mouse model of glioblastoma (GBM) that recapitulates the therapeutic scheme applied to human patients. This models relies on the use of the GL261 mouse GBM line.•We test the relevance of pharmacological inhibition of the Endoplasmic Reticulum stress sensor IRE1 as a potential adjuvant therapeutic approach in GBM using local delivery of the IRE1 RNase inhibitor MKC8866.•We demonstrate that the combination of IRE1 inhibition with irradiation/chemotherapy performs better than irradiation/chemotherapy alone leading to extended survival of the mice.