title: Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates.
abstract: The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is a major target for cancer therapy. As a strategy to induce the maximal inhibition of this pathway in cancer cells, we combined allosteric mTOR inhibitors (rapamycin and RAD001) with a dual PI3K/mTOR kinase inhibitor (PI-103). Both in vitro and in vivo, the combination exhibited more activity than single agents in human ovarian and prostate cancer cells that harbor alterations in the pathway. At the molecular level, combined inhibition of mTOR prevented the rebound activation of Akt that is seen after treatment with rapamycin and its analogues and caused more sustained inhibition of Akt phosphorylation. Furthermore, the combination strongly inhibited the expression of PI3K/Akt/mTOR downstream proteins. In particular, it showed greater activity than the single agents in inhibiting the phosphorylation of 4EBP1, both in vitro and in vivo, resulting in selective inhibition of CAP-dependent translation. A proteomic approach was used to confirm the identification of c-Myc as the key regulator for the reduction in downstream proteins affected by the combined inhibition of mTOR. In conclusion, the combination of a catalytic and an allosteric inhibitor of mTOR shows greater activity, without a concomitant increase in toxicity, than either drug alone, and this may have therapeutic implications for inhibiting this pathway in the clinical setting.
authors: Laboratory of Molecular Pharmacology and Laboratory of Antitumoral Pharmacology, Department of Oncology, and Gene and Protein Biomarkers Unit, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors: Marco
authors: M
authors: Mazzoletti
authors: Francesca
authors: F
authors: Bortolin
authors: Laura
authors: L
authors: Brunelli
authors: Roberta
authors: R
authors: Pastorelli
authors: Silvana
authors: S
authors: Di Giandomenico
authors: Eugenio
authors: E
authors: Erba
authors: Paolo
authors: P
authors: Ubezio
authors: Massimo
authors: M
authors: Broggini