Journal
CANCER BIOLOGY & THERAPY
Volume 7, Issue 12, Pages 1952-1958Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.7.12.6944
Keywords
mTOR inhibitors; erlotinib; survival signaling; Akt; ERK; eIF4E
Categories
Funding
- NIH [RO1 CA118450-01, PO1 CA116676-01]
- Georgia Cancer Coalition Distinguished Cancer Scholar award
- DOD IMPACT award [W81XWH-05-0027]
- BATTLE award [W81XWH-06-1-0303]
- NATIONAL CANCER INSTITUTE [P01CA116676, R01CA118450] Funding Source: NIH RePORTER
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The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Several mTOR inhibitors are currently being tested in cancer clinical trials. Both PI3K/Akt and MEK/ERK signaling regulate mTOR axis. However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors' anticancer efficacy. We are interested in developing strategies for enhancing mTOR-targeted cancer therapy. In this study, we report that mTOR inhibition also induced activations of the MEK/ERK signaling pathway in some cancer cell lines after a prolonged treatment. The combination of rapamycin with the MEK inhibitor U0126 significantly enhanced growth inhibitory effects of cancer cells, suggesting that MEK/ERK activation may counteract mTOR inhibitors' anticancer efficacy. Similarly, the combination of an mTOR inhibitor with the EGF receptor inhibitor erlotinib synergistically inhibited the growth of both human cancer cells in cell cultures and xenografts in nude mice. Moreover, the presence of erlotinib suppressed rapamycin-induced phosphorylation of Akt, ERK and eIF4E as well, implying that erlotinib can suppress mTOR inhibition-induced feedback activation of several survival signaling pathways including Akt, ERK and eIF4E. Thus, we suggest a therapeutic strategy for enhancing mTOR-targeted cancer therapy by preventing mTOR inhibition-induced feedback activation of several survival mechanisms.
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