title: Evidence of mTOR Activation by an AKT-Independent Mechanism Provides Support for the Combined Treatment of PTEN-Deficient Prostate Tumors with mTOR and AKT Inhibitors.
abstract: Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone.
authors: Merck Research Laboratories, Boston, MA.
authors: Weisheng
authors: W
authors: Zhang
authors: Brian B
authors: BB
authors: Haines
authors: Clay
authors: C
authors: Efferson
authors: Joe
authors: J
authors: Zhu
authors: Chris
authors: C
authors: Ware
authors: Kaiko
authors: K
authors: Kunii
authors: Jennifer
authors: J
authors: Tammam
authors: Minilik
authors: M
authors: Angagaw
authors: Marlene C
authors: MC
authors: Hinton
authors: Heike
authors: H
authors: Keilhack
authors: Cloud P
authors: CP
authors: Paweletz
authors: Theresa
authors: T
authors: Zhang
authors: Chris
authors: C
authors: Winter
authors: Sriram
authors: S
authors: Sathyanarayanan
authors: Jonathan
authors: J
authors: Cheng
authors: Leigh
authors: L
authors: Zawel
authors: Stephen
authors: S
authors: Fawell
authors: Gary
authors: G
authors: Gilliland
authors: Pradip K
authors: PK
authors: Majumder