Avaliação do efeito sinérgico a partir da inibição simultânea de EGFR e PI3K/mTOR: uma nova alternativa terapêutica para o tratamento do glioblastoma

Abstract

Glioblastoma (GB) is a malignant and invasive tumor with a high proliferation profile, resulting in a poor prognosis. Due to the high lethality rate and limited therapeutic options, GB shows high mortality. Besides, TMZ-based chemotherapy has significant limitations, such as resistance. In this context, several studies have considered Tyrosine – Kinase Receptor inhibitors (TKRi) against GB. However, monotherapy with TKRi shows limited efficacy and safety. For this purpose, investigating synergistic effects appears as an alternative to increase the potency and safety of anti-tumor drugs. First, our study aims to demonstrate the synergistic effect of the combination of osimertinibe (an irreversible and BBB-permeable EGFR inhibitor) and gedatolisib (PI3K and mTOR dual inhibitor) in a phenotypic assay against five GB cell lines. Secondly, we searched for a synergistic effect on the combination of EGFR inhibitor LASSBio-1971 (planned and synthesized by our lab) and gedatolisib, which were BBB-permeable, considering in vitro prediction based on the HBMEC monolayer model. Although both combinations showed a synergistic effect, LASSBio-1971 appears as a more selective compound: both combinations showed reduced migration and proliferation and induced apoptosis. In conclusion, our in vitro results suggest that the triple inhibition of EGFR, PI3K/mTOR, is a promising therapeutic strategy for GB treatment to be tested in pre-clinical models.