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Rational cotargeting of Pim-1 and Akt in prostate cancer

Paul Toren1, Amina Zoubeidi

  • 1The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.

Expert Review of Anticancer Therapy
|August 30, 2013
PubMed

Insights

Small molecule AKT inhibitors can increase receptor tyrosine kinases in prostate cancer. Pim-1 kinase mediates this effect, suggesting co-targeting strategies for improved cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase/AKT (PI3K/Akt) pathway is crucial in aggressive cancers.
  • Targeting the PI3K/Akt pathway is a key therapeutic strategy, but faces challenges due to feedback mechanisms.
  • Pim-1 kinases are often overexpressed in aggressive and treatment-resistant cancers.

Purpose of the Study:

  • To investigate the role of Pim-1 in the elevation of receptor tyrosine kinases (RTKs) induced by Akt inhibition.
  • To elucidate the mechanism by which Pim-1 mediates this RTK upregulation.
  • To explore potential co-targeting strategies in prostate cancer therapy.

Main Methods:

  • Utilized small molecule AKT inhibitors in prostate cancer models.
  • Assessed the expression and activity of Pim-1 kinase.
  • Investigated the translational regulation of RTKs, focusing on cap-independent mechanisms.

Main Results:

  • Akt inhibition led to the elevation of receptor tyrosine kinases.
  • Pim-1 was identified as a critical mediator of this RTK elevation.
  • This upregulation was found to be mediated, at least in part, by cap-independent translation.

Conclusions:

  • Pim-1 plays a significant role in the feedback loop following Akt inhibition.
  • Understanding this mechanism opens avenues for combination therapies.
  • Co-targeting Pim-1 and PI3K/Akt pathways may overcome treatment resistance in prostate cancer.

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