Inhibition of the mTORC2 and chaperone pathways to treat leukemia.

Blood
Fan ZhangBing Su

Abstract

Constitutive activation of the kinases Akt or protein kinase C (PKC) in blood cancers promotes tumor-cell proliferation and survival and is associated with poor patient survival. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) regulates the stability of Akt and conventional PKC (cPKC; PKCα and PKCβ) proteins by phosphorylating the highly conserved turn motif of these proteins. In cells that lack mTORC2 function, the turn motif phosphorylation of Akt and cPKC is abolished and therefore Akt and cPKC protein stability is impaired. However, the chaperone protein HSP90 can stabilize Akt and cPKC, partially rescuing the expression of these proteins. In the present study, we investigated the antitumor effects of inhibiting mTORC2 plus HSP90 in mouse and human leukemia cell models and show that the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) preferentially inhibits Akt and cPKC expression and promotes cell death in mTORC2 deficient pre-B leukemia cells. Furthermore, we show that 17-AAG selectively inhibits mTORC2 deficient leukemia cell growth in vivo. Finally, we show that the mTOR inhibitors rapamycin and pp242 work together with 17-AAG to inhibit leukemia cell growth to a greater extent than either drug alone. The...Continue Reading

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Citations

Jun 26, 2014·Journal of Biochemistry·Takayuki HoshiiAtsushi Hirao
Nov 14, 2014·Open Biology·Becky Pinjou TsaiMarian L Waterman
Mar 6, 2013·Journal of Cellular Physiology·Anya Alayev, Marina K Holz
Sep 23, 2014·BioMed Research International·Yanan ZhangJing Liu
Feb 2, 2019·Cellular & Molecular Immunology·Man LiBing Su

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