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Inhibition of the mTORC2 and chaperone pathways to treat leukemia

Fan Zhang1, Adam S Lazorchak, Dou Liu

  • 1Department of Immunobiology and Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520, USA.

Blood
|May 9, 2012
PubMed

Insights

Combining mTOR inhibitors with HSP90 inhibitors shows promise for treating blood cancers. This dual inhibition effectively reduces leukemia cell growth by targeting key proteins like Akt and PKC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Constitutive activation of Akt and protein kinase C (PKC) drives proliferation and survival in blood cancers, correlating with poor patient outcomes.
  • Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) stabilizes Akt and conventional PKC (cPKC) via phosphorylation of their turn motif.
  • Loss of mTORC2 function impairs Akt and cPKC stability, although heat shock protein 90 (HSP90) can partially rescue their expression.

Purpose of the Study:

  • To investigate the antitumor effects of combined mTORC2 and HSP90 inhibition in leukemia models.
  • To evaluate the efficacy of HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) in mTORC2-deficient leukemia cells.
  • To determine the synergistic effects of combining mTOR inhibitors with 17-AAG.

Main Methods:

  • Utilized mouse and human leukemia cell models.
  • Administered the HSP90 inhibitor 17-AAG.
  • Employed mTOR inhibitors rapamycin and pp242.
  • Assessed protein expression, cell death, and tumor growth in vivo.

Main Results:

  • 17-AAG preferentially inhibited Akt and cPKC expression, inducing cell death in mTORC2-deficient pre-B leukemia cells.
  • 17-AAG demonstrated selective inhibition of mTORC2-deficient leukemia cell growth in vivo.
  • Combined treatment with mTOR inhibitors (rapamycin, pp242) and 17-AAG resulted in greater inhibition of leukemia cell growth than monotherapy.

Conclusions:

  • Inhibition of mTORC2 and HSP90 exhibits significant antitumor activity in leukemia.
  • Combined inhibition of mTOR and HSP90 offers a synergistic approach to leukemia treatment.
  • These findings provide a mechanistic and clinical rationale for combining mTOR inhibitors and chaperone protein inhibitors in treating human blood cancers.

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