A Pharmacologic Approach Against Glioblastoma-A Synergistic Combination of a Quinoxaline-Based and a PI3K/mTOR Dual Inhibitor.

Glioblastoma (GB) is the most common malignant primary CNS tumor with a fast-growing and invasive profile. As a result of the poor prognosis and limited therapy available, glioblastoma shows a high mortality rate. Given the scarcity of effective chemotherapy options, multiple studies have explored the potential of tyrosine kinase inhibitors. To mitigate resistance and improve potency and selectivity, we proposed the combination of a potent irreversible epidermal growth factor receptor inhibitor-LASSBio-1971-and a potent phosphatidylinositol-3-kinase/mammalian target of rapamycin dual inhibitor-Gedatolisib-through an in vitro phenotypic study using five human GB lines. Here, we aimed to establish the cytotoxic potency, selectivity, and effect on proliferation, apoptosis, migration, and the cell cycle. Our data showed the cytotoxic potency of Gedatolisib and LASSBio-1971 and improved selectivity in the GB cell lines. They highlighted the synergistic response from their combination and its impact on migration reduction, G0/G1 cell cycle arrest, GB cytotoxicity, and apoptosis-inducing effects for different GB cell lines. The drug combination studies in phenotypic in vitro models made it possible to suggest a new potential treatment for glioblastoma that justifies further safety in in vivo phases of preclinical trials with the combination.