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Updated: Jun 18, 2025

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
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Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma

Catherine A Behrmann1, Kelli N Ennis1, Pranjal Sarma1

  • 1Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Cancer Research Communications
|August 1, 2024
PubMed

Insights

Targeting ribosomal protein S6 kinase 1 (S6K1) and AXL receptor tyrosine kinase with LY-2584702 and BMS-777607 inhibits glioblastoma growth. This combination therapy overcomes resistance by disrupting metabolic functions in PTEN-deficient tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • PTEN-deficient glioblastoma (GBM) exhibits intrinsic resistance to targeted therapies due to redundant signaling networks.
  • Sustained metabolic functions by these networks contribute to therapeutic resistance in GBM.

Purpose of the Study:

  • To identify a kinase-targeting strategy to overcome resistance and inhibit the growth of PTEN-deficient glioblastoma.
  • To investigate the combined effect of inhibiting S6K1 and AXL on GBM metabolism and growth.

Main Methods:

  • Utilized LY-2584702 to inhibit ribosomal protein S6 kinase 1 (S6K1) and BMS-777607 to inhibit receptor tyrosine kinase AXL.
  • Employed genetic inactivation studies to map signaling networks and identify signal transmitters.
  • Performed kinome-wide ATP binding and substrate phosphorylation analyses to confirm inhibitor specificities and downstream effects.

Main Results:

  • Coordinated inhibition of S6K1 and AXL suppressed glucose flux to pyrimidine biosynthesis, a critical metabolic pathway.
  • Both S6K1 and S6K2 were identified as key signal transmitters in PTEN-deficient GBM.
  • Combination therapy effectively reduced glioblastoma tumor growth by circumventing signal transduction redundancy.

Conclusions:

  • Combination targeting of S6K1 and AXL offers a novel kinase-directed therapeutic approach for PTEN-deficient GBM.
  • This strategy effectively disrupts metabolic functions and reduces tumor growth by overcoming inherent resistance mechanisms.

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