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Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis

Niccolò Bartalucci1,2,3, Laura Calabresi1,2,3, Manjola Balliu1,2,3

  • 1CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.

Oncotarget
|December 13, 2017
PubMed

Insights

Ruxolitinib shows limited efficacy in myeloproliferative neoplasms. Combining PI3K/mTOR inhibitors with ruxolitinib overcomes resistance by fully inhibiting STAT5 phosphorylation, offering a novel treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Myeloproliferative neoplasms (MPNs) with JAK2V617F mutation are driven by the JAK/STAT pathway.
  • Ruxolitinib, a JAK1/JAK2 inhibitor, offers clinical benefits but lacks disease-modifying effects and faces resistance.
  • Novel therapeutic strategies are needed for MPNs due to incomplete responses to current treatments.

Purpose of the Study:

  • To investigate the mechanisms of ruxolitinib resistance in JAK2V617F mutated cells.
  • To identify novel therapeutic targets and strategies for improving treatment efficacy in MPNs.
  • To evaluate the efficacy of combination therapy targeting JAK/STAT, PI3K, and mTOR pathways.

Main Methods:

  • Utilized JAK2V617F mutated cell lines, primary patient cells, and JAK2V617F knock-in mouse models.
  • Investigated STAT5 phosphorylation and its regulation by PI3K/mTOR pathways, Protein Phosphatase 2A, and CIP2A.
  • Assessed the efficacy of combination therapy with ruxolitinib, PI3K inhibitor (BKM120), and mTOR inhibitor (RAD001).

Main Results:

  • Ruxolitinib causes incomplete STAT5 inhibition in JAK2V617F cells due to persistent phosphorylated serine residues.
  • PI3K/mTOR signaling, involving Protein Phosphatase 2A and CIP2A, drives STAT5b serine phosphorylation.
  • Increased CIP2A levels correlate with JAK2V617F mutation; its downregulation is linked to clinical response in myelofibrosis patients treated with RAD001.
  • Combination therapy with ruxolitinib, BKM120, and RAD001 achieved maximal STAT5 phosphorylation inhibition and improved efficacy in preclinical models.

Conclusions:

  • Ruxolitinib's incomplete STAT5 inhibition contributes to treatment resistance in MPNs.
  • Targeting PI3K/mTOR pathways, alongside JAK inhibition, offers a promising strategy to overcome resistance.
  • Combination therapy demonstrates potential for maximal STAT5 inhibition and improved outcomes in JAK2V617F-mutated MPNs, warranting clinical trials.
Keywords:
MPNPI3K/mTOR inhibitorsSTAT5phosphorylationruxolitinib

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