S6k Feedback Regulation Of The Receptor Tyrosine Kinase Axl In Pten-Deficient Glioblastoma
Neuro-oncology(2020)
摘要
Abstract Glioblastoma multiforme (GBM), the most aggressive type of malignant brain cancer in adults, harbors frequent mutations and/or deletions in the tumor suppressor gene PTEN leading to therapeutic resistance. In PTEN-deficient GBM, mTOR complex 1 (mTORC1) and the S6 kinases (S6Ks) mediate increased metabolism and apoptosis resistance. Previously we established that combining the LY-2584702 inhibitor of S6K1 with the BMS-777607 inhibitor of the AXL receptor tyrosine kinase (RTK) was selectively cytotoxic for PTEN-deficient GBM. Here we determined the impact of these inhibitors on S6K1 and S6K2 signal transduction and tumor cell metabolism. While combination of LY-2584702 with BMS-777607 was sufficient to prevent S6K phosphorylation of ribosomal protein S6 (rpS6), treatment with either drug as a single agent was not sufficient to suppress rpS6 phosphorylation. Genetic inactivation of S6Ks revealed that inactivation of S6K2 cooperated with LY-2584702 to prevent S6K substrate phosphorylation. Similarly, persistent S6K signaling in BMS777607-treated GBM cells was significantly reduced when S6K2 was targeted. These results indicate that S6K2 integrates signal transduction inputs from both PTEN-regulated and AXL-regulated pathways. Metabolomic analysis revealed combination effects of S6K and AXL inhibitors in reducing nucleotide precursor metabolic flux. We therefore propose that combination inhibition of S6K and AXL signaling compromises S6K-dependent nucleotide synthesis in PTEN-deficient GBM.
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关键词
receptor tyrosine,axl,pten-deficient
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