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Accordingly, mTOR inhibitors are proposed for combined therapeutic strategies in CML. The major caveat in the use of mTOR inhibitors for cancer therapy comes from the induction of an mTOR\u2010phosphatidylinositol 3 kinase (PI3k) feedback loop driving the retrograde activation of Akt. Here we show that the rapamycin derivative RAD 001 (everolimus, Novartis Institutes for Biomedical Research) inhibits mTOR and, more importantly, revokes mTOR late re\u2010activation in response to IM. RAD 001 interferes with the assembly of both mTOR complexes: mTORC1 and mTORC2. The inhibition of mTORC2 results in the de\u2010phosphorylation of Akt at Ser<jats:sup>473<\/jats:sup> in the hydrophobic motif of C\u2010terminal tail required for Akt full activation and precludes Akt re\u2010phosphorylation in response to IM. Moreover, RAD 001\u2010induced inhibition of Akt causes the de\u2010phosphorylation of tuberous sclerosis tumor suppressor protein TSC2 at 14\u20103\u20103 binding sites, TSC2 release from 14\u20103\u20103 sigma (restoring its inhibitory function on mTORC1) and nuclear import (promoting the nuclear translocation of cyclin\u2010dependent kinase [CDK] inhibitor p27<jats:sup>Kip1<\/jats:sup>, the stabilization of p27<jats:sup>Kip1<\/jats:sup> ligand with CDK2, and the G<jats:sub>0<\/jats:sub>\/G<jats:sub>1<\/jats:sub> arrest). RAD 001 cytotoxicity on cells not expressing the BCR\u2010ABL fusion gene or its p210 protein tyrosine kinase (TK) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect. J. Cell. Biochem. 109: 320\u2013328, 2010. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.22380","type":"journal-article","created":{"date-parts":[[2009,12,11]],"date-time":"2009-12-11T20:11:49Z","timestamp":1260562309000},"page":"320-328","source":"Crossref","is-referenced-by-count":24,"title":["RAD 001 (everolimus) prevents mTOR and Akt late re\u2010activation in response to imatinib in chronic myeloid 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