cc214-2 and Brain-Neoplasms

Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.

Topics: Adaptation, Physiological; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Butadienes; Dasatinib; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Gene Expression Profiling; Genes, erbB-1; Glioblastoma; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Models, Biological; Molecular Targeted Therapy; Multiprotein Complexes; Mutation; Neoplasm Proteins; Nitriles; Phosphoproteins; Protein Kinase Inhibitors; Proteomics; Pyrazines; Selection, Genetic; Signal Transduction; Single-Cell Analysis; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays