Multiple lesions in receptor tyrosine kinase pathway determine glioblastoma response to pan-ERBB inhibitor PF-00299804 and PI3K/mTOR dual inhibitor PF-05212384.

ABSTRACT: A novel pan ERBB inhibitor PF-00299804 (dacomitinib) is currently in phase II clinical trials in glioblastoma multiforme (GBM) patients; however its pre-clinical efficacy in GBMs has not been tested. In this study, we evaluated the efficacy of dacomitinib alone or in combination with PI3K/mTOR dual inhibitor PF-05212384 in GBM and assessed the mechanisms of resistance and the molecular determinants of response. A panel of established and patient derived primary GBM lines that present different molecular profiles and also the GBM lines engineered to express EGFRvIII mutant or PTEN were treated with either dacomitinib, PF-05212384, or combination and assessed for their viability and changes in EGFR/PI3K/mTOR signaling. We show that dacomitinib significantly reduced phosphorylated EGFR in all

SUBMITTER: Zhu Y 

PROVIDER: S-EPMC4049797 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature