Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Cell Rep. 2017 Feb 28;18(9):2088-2095. doi: 10.1016/j.celrep.2017.02.022.

Abstract

Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed the rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.

Keywords: AD80; AXL; BMS-777607; LY-2779964; PF4708671; Pten; S6K1; TAM; glioblastoma; leukemia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Gene Knockdown Techniques / methods
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Leukemia, T-Cell / drug therapy
  • Leukemia, T-Cell / metabolism
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism*
  • PTEN Phosphohydrolase / deficiency*
  • Phosphorylation / drug effects
  • Pyridones / pharmacology
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • AD80 compound
  • Aminopyridines
  • Antineoplastic Agents
  • Heterocyclic Compounds, 4 or More Rings
  • N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
  • Pyridones
  • TOR Serine-Threonine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Ribosomal Protein S6 Kinases, 70-kDa
  • PTEN Phosphohydrolase