Deregulation and activation of the
phosphoinositide 3-kinase (PI3K)/Akt/mammalian (or mechanistic) target of
rapamycin (mTOR) pathway have a major role in proliferation and cell survival in
breast cancer. However, as single agents,
mTOR inhibitors have had modest antitumor efficacy. In this study, we evaluated the effects of vertical inhibition of mTOR and Akt in
breast cancer cell lines and xenografts. We assessed the effects of mTOR inhibitor
rapamycin and Akt inhibitor
MK-2206, given as single drugs or in combination, on cell signaling, cell proliferation and apoptosis in a panel of
cancer cell lines in vitro. The antitumor efficacy was tested in vivo. We demonstrated that
MK-2206 inhibited Akt phosphorylation, cell proliferation and apoptosis in a dose-dependent manner in
breast cancer cell lines.
Rapamycin inhibited S6 phosphorylation and cell proliferation, and resulted in lower levels of apoptosis induction. Furthermore, the combination treatment inhibited phosphorylation of Akt and S6, synergistically inhibited proliferation and induced apoptosis with a higher efficacy. In vivo combination inhibited
tumor growth more than either agent alone. Our data suggest that a combination of Akt and
mTOR inhibitors have greater antitumor activity in
breast cancer cells, which may be a viable approach to treat patients.