Tmod-01. functional kinome characterization of a diverse panel of glioblastoma models

Glioblastoma (GBM) is the most common malignant primary brain tumor. Treatments are limited and clinical efficacy of kinase inhibitors has been disappointing. The molecular heterogeneity of GBM is well characterized, but knowledge of the GBM kinome is limited. To this end, we utilized a chemical proteomics method consisting of multiplex inhibitor beads and mass spectrometry (MIB-MS) to assess the functional state of tumor kinomes en masse, both in the presence (dynamic profiling) and absence (baseline profiling) of kinase inhibitors. Baseline kinome profiling of patient derived xenografts, established cell lines (ECL), isogenic mutant immortalized human astrocytes (NHA), non-germline genetically-engineered mouse (nGEM) astrocytes, and human GBM demonstrated extensive heterogeneity. Two major subtypes were apparent in human tumors with differential functional expression of RTK (PDGFRβ, IGF1R, MET, EGFR) and their MAPK (ERK1/2 and BRAF) and PI3K (AKT1-3, MTOR) effector arms. We therefore tested the efficacy of MAPK and PI3K inhibition using brain penetrant inhibitors of MEK (selumetinib) and PI3K (buparlisib), in ECL (U251, U87, and LN229), NHA with and without constitutively active mutants in HRAS ± AKT, and nGEM astrocytes harboring homozygous deletion of Trp53 and Nf1 (Trp53;Nf1Del) or T121, KrasG12D and Pten deletion (TRP). Selumetinib IC50 ranged from 2–23 µM, while buparlisib IC50 ranged from 0.7–1.8 µM in all four model syste...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MODELS Source Type: research