TI - Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells . AB - Elevated epidermal growth factor receptor ( EGFR ) and mammalian target of rapamycin ( mTOR ) signaling are known to contribute to the malignant properties of glioblastoma multiforme ( GBM ) , which include uncontrolled cell proliferation and evasion of apoptosis . Small molecule inhibitors that target these protein kinases have been evaluated in multiple clinical trials for cancer patients , including those with GBM . Here we have examined the cellular and molecular effects of a combined kinase inhibition of mTOR ( rapamycin ) and EGFR (EKI-785) in U87 and U251 GBM cells . Simultaneous treatment with rapamycin and EKI-785 results in synergistic antiproliferative as well as proapoptotic effects . At a molecular level , rapamycin alone significantly decreases S6 phosphorylation , whereas EKI-785 alone promotes substantially reduced signal transducer and activator of transcription ( STAT3 ) phosphorylation . Treatment with rapamycin alone also increases Akt phosphorylation on Ser-473 , but this effect is blocked by a simultaneous administration of EKI-785 . Individually , EKI-785 diminishes while rapamycin promotes the binding of the translation inhibitor eukaryotic initiation factor 4E binding protein ( 4EBP1 ) to the eukaryotic translation initiation factor 4E ( eIF4E ) . In spite of these opposing effects , the highest level of 4EBP1-eIF4E binding occurs with the combination of the two inhibitors . These results indicate that the inhibition of EGFR and mTOR has distinct as well as common signaling consequences and provides a molecular rationale for the synergistic antitumor effects of EKI-785 and rapamycin administration .