title: 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 the GBM lines but did not show a dose-dependent response on cell viability in a majority of the lines tested. Multiple lesions in the receptor tyrosine kinases (RTKs) pathway including PTEN mutation, co-activation of RTKs, and EGFRvIII mutation resulted in unaltered active status of PI3K/mTOR in the GBM lines even in the presence of EGFR inhibition. Blocking PI3K/mTOR dramatically inhibited cell proliferation in most GBM lines and enhanced dacomitinib induction of apoptosis in a GBM line that has both EGFR amplification and EGFR-independent PI3K activation. These data suggest molecular profiling of EGFR/PI3K/PTEN status to select GBM patients for EGFR or/and PI3K/mTOR targeted therapies.
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Department of Radiology; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Molecular Neurotherapy and Imaging Laboratory; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Department of Radiology; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Department of Neurology; Massachusetts General Hospital; Harvard Medical School; Boston, MA USA; Harvard Stem Cell Institute; Harvard University; Cambridge, MA USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D052999:Quinazolinones / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; D018739:Oncogene Proteins v-erbB; D000081082:Phosphoinositide-3 Kinase Inhibitors; D052999:Quinazolinones; D014227:Triazines; C525726:dacomitinib; C549060:gedatolisib; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases
keywords: EGFR; PF-00299804; PF-05212384; PI3K; dacomitinib; glioblastoma (GBM); mTOR