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Targeting mTORC1-mediated metabolic addiction overcomes fludarabine resistance in malignant B cells

Arishya Sharma1, Allison J Janocha2, Brian T Hill3

  • 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, Ohio.

Molecular Cancer Research : MCR
|July 26, 2014
PubMed
Abstract

Insights

Targeting metabolic reprogramming in cancer, this study found that resistance to fludarabine in chronic lymphocytic leukemia cells involves increased pyrimidine biosynthesis. Inhibiting this pathway and mitochondrial respiration shows promise for overcoming chemoresistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • MTOR complex-1 (mTORC1) activation is common in cancers, but clinical use of rapalogs is limited by compensatory survival pathway activation.
  • Acquired resistance to fludarabine (Flu), a chemotherapy for chronic lymphocytic leukemia (CLL), was investigated as a model to explore therapeutic strategies targeting downstream mTORC1 effectors.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to fludarabine in chronic lymphocytic leukemia (CLL) by examining the role of mTORC1 signaling and downstream metabolic pathways.
  • To identify potential therapeutic targets for overcoming fludarabine resistance by understanding the metabolic reprogramming associated with this resistance.

Main Methods:

  • Assessed mTORC1 activation marker phospho-p70S6K (RPS6KB1) in B-cell lines, isogenic fludarabine-resistant (FluR) derivatives, and primary CLL cells.
  • Measured glycolysis and oxidative phosphorylation rates in fludarabine-sensitive (FluS) and FluR cells.
  • Investigated the role of dihydroorotate dehydrogenase (DHODH) in de novo pyrimidine biosynthesis and its link to mitochondrial respiration.
  • Examined the effect of mTORC1 inhibition, p70S6K knockdown, and inhibition of de novo pyrimidine biosynthesis or mitochondrial respiration on cell viability.

Main Results:

  • Elevated phospho-p70S6K predicted fludarabine resistance and was associated with increased glycolysis and oxidative phosphorylation in FluR cells.
  • Increased oxidative phosphorylation in FluR cells was primarily linked to de novo pyrimidine biosynthesis, not ATP synthesis, via dihydroorotate dehydrogenase.
  • mTORC1 promotes pyrimidine biosynthesis through p70S6K-mediated phosphorylation of CAD (Ser1859), leading to increased S-phase progression.
  • Pharmacological inhibition of de novo pyrimidine biosynthesis or mitochondrial respiration, and p70S6K knockdown, selectively killed FluR cells but not FluS cells.

Conclusions:

  • This study reveals a novel link between mTORC1-mediated metabolic reprogramming and fludarabine resistance in CLL.
  • mTORC1/p70S6K-dependent regulation of de novo pyrimidine biosynthesis and mitochondrial respiration represents a potential therapeutic vulnerability in fludarabine-resistant CLL.

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