title: A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia.
abstract: Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream effectors, Akt and mechanistic target of rapamycin (mTOR), is aberrantly activated in acute myeloid leukemia (AML) patients, where it contributes to leukemic cell proliferation, survival, and drug-resistance. Thus, inhibiting mTOR signaling in AML blasts could enhance their sensitivity to cytotoxic agents. Preclinical data also suggest that allosteric mTOR inhibition with rapamycin impaired leukemia initiating cells (LICs) function. In this study, we assessed the therapeutic potential of a combination consisting of temsirolimus [an allosteric mTOR complex 1 (mTORC1) inhibitor] with clofarabine, a nucleoside analogue with potent inhibitory effects on both ribonucleotide reductase and DNA polymerase. The drug combination (CLO-TOR) displayed synergistic cytotoxic effects against a panel of AML cell lines and primary cells from AML patients. Treatment with CLO-TOR induced a G₀/G₁-phase cell cycle arrest, apoptosis, and autophagy. CLO-TOR was pro-apoptotic in an AML patient blast subset (CD34⁺/CD38⁻/CD123⁺), which is enriched in putative leukemia initiating cells (LICs). In summary, the CLO-TOR combination could represent a novel valuable treatment for AML patients, also in light of its efficacy against LICs.
authors.affiliation: Institute of Molecular Genetics, National Research Council, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lonetti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Teti
authors.forename: Ester
authors.initials: E
authors.lastname: Orsini
authors.forename: Daniela
authors.initials: D
authors.lastname: Bressanin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cappellini
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Tazzari
authors.forename: Andrea
authors.initials: A
authors.lastname: Ognibene
authors.forename: Mirella
authors.initials: M
authors.lastname: Falconi
authors.forename: Pasqualepaolo
authors.initials: P
authors.lastname: Pagliaro
authors.forename: Ilaria
authors.initials: I
authors.lastname: Iacobucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000227:Adenine Nucleotides / Q000494:pharmacology; D000494:Allosteric Regulation; D018952:Antigens, CD34 / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001087:Arabinonucleosides / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D000077866:Clofarabine; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000227:Adenine Nucleotides; D018952:Antigens, CD34; D000964:Antimetabolites, Antineoplastic; D001087:Arabinonucleosides; D039562:Eukaryotic Initiation Factor-4F; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; C489427:MYC protein, human; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C401859:temsirolimus; D000077866:Clofarabine; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D020123:Sirolimus