The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL)

Cancer Lett. 2017 Apr 28;392:9-16. doi: 10.1016/j.canlet.2017.01.035. Epub 2017 Feb 1.

Abstract

Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting.

Keywords: Gedatolisib; Leukemia; PF 05212384; PI3K/mTOR; T-ALL.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Jurkat Cells
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy
  • Morpholines / pharmacology*
  • Phosphatidylinositol 3-Kinase / genetics
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Interaction Maps
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Triazines / pharmacology*
  • Tumor Burden / drug effects
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Triazines
  • gedatolisib
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase