mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt

TLDR

The PI3K/Akt/mTOR pathway is activated by insulin/IGF‑I receptors, and although tumors with PI3K/Akt mutations are hypersensitive to mTOR inhibitors in preclinical models, clinical efficacy is modest due to feedback down‑regulation of insulin receptor substrate‑1. The study aimed to determine whether rapamycin‑induced loss of IRS‑1 leads to Akt activation and whether blocking IGF‑I receptor signaling could improve mTOR inhibitor efficacy. mTOR inhibition restores IRS‑1 expression, removes feedback inhibition, and activates Akt in cell lines and patient tumors; IGF‑I receptor blockade prevents this Akt activation and sensitizes tumors, whereas IGF‑I reverses rapamycin’s antiproliferative effects, indicating that feedback down‑regulation of RTK signaling is common in mTOR‑activated tumors. Cancer Res 2006; 66(3): 1500‑8.

Abstract

Abstract Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity. (Cancer Res 2006; 66(3): 1500-8)