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Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

Benedito A Carneiro1, Jason B Kaplan, Jessica K Altman

  • 1a Robert H Lurie Comprehensive Cancer Center of Northwestern University ; Chicago , IL , USA.

Cancer Biology & Therapy
|March 25, 2015
PubMed

Insights

Targeting the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway shows promise for acute myeloid leukemia (AML) treatment. Combination therapies may be necessary to overcome resistance mechanisms in leukemia cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Acute myeloid leukemia (AML) pathogenesis involves complex intracellular signaling.
  • The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is frequently dysregulated in AML.
  • This pathway regulates critical cellular processes like proliferation, metabolism, and survival.

Purpose of the Study:

  • To review preclinical and clinical data on targeting the PI3K/AKT/mTOR pathway in AML.
  • To address challenges related to negative feedback loops contributing to leukemic cell survival.
  • To explore the potential of combination therapies for AML treatment.

Main Methods:

  • Review of existing preclinical studies on PI3K/AKT/mTOR inhibitors in AML.
  • Analysis of clinical trial data investigating PI3K/AKT/mTOR pathway inhibitors.
  • Discussion of molecular mechanisms, including negative feedback loops.

Main Results:

  • Pharmacologic inhibitors targeting the PI3K/AKT/mTOR pathway have been developed.
  • Currently, no PI3K/AKT/mTOR inhibitors have an established role in AML treatment.
  • Negative feedback loops contribute to leukemic cell survival despite pathway inhibition.

Conclusions:

  • Targeting the PI3K/AKT/mTOR pathway is a high-interest strategy for AML therapy.
  • Combination therapies may be required to effectively block negative feedback loops.
  • Further research is needed to optimize therapeutic strategies targeting this pathway in AML.
Keywords:
AMLAML, acute myeloid leukemiaAcute myeloid leukemiaAktHDAC, histone deacetylaseMAPKMNK, MAPK-interacting kinasePDK1, phosphoinositide-dependent protein kinase-1PI3KPI3K, phosphatidylinositol 3-kinasemTORmTOR, mammalian target of rapamycintargeted therapy

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