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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, RESULTS. Meshes: Aniline Compounds, Biomarkers, Tumor, Brain Neoplasms, Cell Line, Tumor, Cell Survival, Cohort Studies, DNA Mutational Analysis, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Glioblastoma, High-Throughput Nucleotide Sequencing, Humans, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Morpholines, Mutation, Neoplastic Stem Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, Proteome, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, TOR Serine-Threonine Kinases, Tumor Suppressor Protein p53.
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Are tP53 mutated glioblastoma stem-like cell cultures sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2? Context: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs). We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged.
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Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored. Final Decision: yes