RAD 001 (everolimus) prevents mTOR and Akt late re-activation in response to imatinib in chronic myeloid leukemia.
The mammalian target of rapamycin (mTOR) is one target of BCR-ABL fusion gene of chronic myeloid leukemia (CML). Moreover, it drives a compensatory route to Imatinib mesylate (IM) possibly involved in the progression of leukemic progenitors towards a drug-resistant phenotype. 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-phosphatidylinositol 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-activation 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-phosphorylation of Akt at Ser(473) in the hydrophobic motif of C-terminal tail required for Akt full activation and precludes Akt re-phosphorylation in response to IM. Moreover, RAD 001-induced inhibition of Akt causes the de-phosphorylation of tuberous sclerosis tumor suppressor protein TSC2 at 14-3-3 binding sites, TSC2 release from 14-3-3 sigma (restoring its inhibitory function on mTORC1) and nuclear import (promoting the nuclear translocation of cyclin-dependent kinase [CDK] inhibitor p27(Kip1), the stabilization of p27(Kip1) ligand with CDK2, and the G(0)/G(1) arrest). RAD 001 cytotoxicity on cells not expressing the BCR-ABL fusion gene or its p210 protein tyrosine kinase (TK) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect.
Mancini
Manuela
M
Dipartimento di Ematologia e Scienze Oncologiche "Lorenzo e Ariosto Seràgnoli," University of Bologna-Medical School, Bologna, Italy. mancini_manu@yahoo.com
Petta
Sara
S
Martinelli
Giovanni
G
Barbieri
Enza
E
Santucci
Maria A
MA
D048948:14-3-3 Proteins; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004347:Drug Interactions; D004351:Drug Resistance; D000068338:Everolimus; D005092:Exonucleases / Q000378:metabolism; D005095:Exoribonucleases; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006410:Hematopoiesis; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007928:Lethal Dose 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D023461:Myeloid Progenitor Cells; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; C504923:Crtc2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D010879:Piperazines; D011506:Proteins; D011743:Pyrimidines; C000624653:TSC2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate; D000068338:Everolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D016044:Fusion Proteins, bcr-abl; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D020123:Sirolimus