Activation of Akt and eIF4E Survival Pathways by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition

Abstract

The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor. (Cancer Res 2005; 65(16): 7052-8)

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

“…In H460, H596, H1299, H1650, SKMES-1 characterized by maintaining S6K phosphorylation after gefitinib treatment, everolimus inhibited phosphorylation of S6K and slowed proliferation, albeit to different extents especially at the lower doses. This result is in agreement with that reported by Sun et al on H460 and H1299 cell lines treated with rapamycin [39]. The high basal level of p-AKT observed in H1650 and SKMES-1 may be associated with the higher sensitivity to everolimus as reported in ovarian cancer cells [40] and in breast cancer cells [41].…”

“…It is recognized that mTOR inhibition induces insulin receptor substrate-1 expression and inhibits a normally negative feedback loop resulting in AKT activation in some cancer cell lines [39,42].…”

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

“…This discovery provided solid evidence that rapamycin does not completely inhibit mTOR function. In addition, a recent investigation showed that the inhibition of mTOR by rapamycin triggered the activation of survival signaling pathways, including the Akt pathway, and that this activation may contribute to drug resistance (Sun et al, 2005). This phenomenon provides support for the idea that mTOR has a positive role in regulating Akt phosphorylation that is not shared with raptor but possibly is shared with rictor (Guertin and Sabatini, 2005).…”

Oncogenic signaling of class I PI3K isoforms

“…Inhibition of TOR relieves a negative feedback loop that targets IRS-1 and leads to elevated phosphorylation of Akt. Removal of this negative feedback may underlie the poor clinical responses of cancer patients treated with rapamycin (Haruta et al, 2000;Sun et al, 2005;O'Reilly et al, 2006). Combined inhibition of PI3K and TOR is more effective in reducing cancer cell growth than inhibition of either target alone (Sun et al, 2005;Fan and Weiss, 2006;.…”