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Dear editor,
Here we submit a manuscript entitled “Feedback loops blockade potentiates antitumor
activity of a novel AKT1 inhibitor DC120 in human liver cancer cells and nude mice
xenografts” to you for your consideration to be published in ONCOTARGET.
In the present study, we reported a novel AKT1 inhibitor DC120 and its antitumor
mechanism and clarified resistant mechanism of the ATP-competitive AKT inhibitors.
Unexpectedly, AKT inhibitors both DC120 and GDC0068 induced hyperphosphorylation of
AKT, which might be common characters of the ATP-competitive inhibitors. Moreover,
DC120 activated mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway
via Ca2+/calmodulin (CaM)/signaling to human vacuolar protein sorting 34 (hVps34) due to
AKT inhibition. DC120 also attenuated the inhibitory effect of AKT on C-Raf by decreasing
the phosphorylation of C-Raf at Ser259 and activated the mitogen-activated protein kinase
(MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 were not
mutually dependent and the combination of DC120 with mTORC1 inhibitor and/or MEK
inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. These
results indicated that a combination of AKT, mTORC1 and/or MEK inhibitors would be a
promising therapeutic strategy for liver cancer treatment.
All authors have contributed significantly and agreed with the content of the manuscript. This
work described has not been published or submitted elsewhere for publication, in whole or in
part. We believe that this would be interested to the readers of ONCOTARGET and your
favorable consideration would be greatly appreciated.
Sincerely yours,
Xiao-Feng Zhu, M.D. & PhD