K. Yu et al., mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer, ENDOCR-R CA, 8(3), 2001, pp. 249-258
The mammalian target of rapamycin (mTOR) is a central regulator of GI cell
cycle protein synthesis that precedes commitment to normal cellular replica
tion. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a r
apamycin ester that inhibits mTOR function, on the proliferation of a panel
of breast cancer cell lines. Six of eight lines studied were sensitive (IC
(50)less than or equal to 50 nM) and two lines were resistant (IC50>1.0 muM
) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D
), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549),
and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lin
es (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM
) inhibited mTOR function in both a sensitive and a resistant line. In nu/n
u mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but
not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779
resulted in a decrease in D-type cyclin and c-myc levels and an increase in
p27(kip-1) levels. There was good correlation between activation of the Ak
t pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6
kinase, which is downstream of Akt, may also have conferred CCI-779 sensit
ivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a g
ood target for breast cancer therapy, especially in tumors with Akt activat
ion resulting from either growth factor dependency or loss of PTEN function
.