title: Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.
abstract: Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL.
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacovelli
authors.affiliation: Hematology, "Sant'Andrea" Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Allegretti
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Mirabilii
authors.affiliation: Hematology, "Sant'Andrea" Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Licchetta
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bergamo
authors.affiliation: Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rinaldo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ann
authors.initials: A
authors.lastname: Zeuner
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.affiliation: Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Hematology, "Sant'Andrea" Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Tafuri
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D032701:Biomimetics; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C401859:temsirolimus; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: BH3 mimetic resistance; Mcl-1; acute lymphoblastic leukemia; mTOR inhibition; targeted therapies