Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo

K. Schuster, J. Zheng, A. A. Arbini, Chengcheng Zhang, Pier P Scaglioni

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway.

Original languageEnglish (US)
Article numbere34
JournalBlood Cancer Journal
Volume1
Issue number9
DOIs
StatePublished - Sep 1 2011

Keywords

  • CML
  • MTORC1/2
  • PI3K inhibitors
  • Targeted leukemia therapy

ASJC Scopus subject areas

  • Hematology
  • Oncology

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