Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia
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Stefano Iacovelli1,*, Maria Rosaria Ricciardi2,*, Matteo Allegretti1, Simone Mirabilii1, Roberto Licchetta2, Paola Bergamo1, Cinzia Rinaldo3, Ann Zeuner4, Robin Foà1, Michele Milella5, James A. McCubrey6, Alberto M. Martelli7, Agostino Tafuri2
1Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Italy
2Hematology, “Sant’Andrea” Hospital - Sapienza University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy
3Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
4Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
5Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy
6Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
7Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
*These authors have contributed equally to this work
Agostino Tafuri, e-mail: [email protected]
Keywords: acute lymphoblastic leukemia, targeted therapies, BH3 mimetic resistance, mTOR inhibition, Mcl-1
Received: April 09, 2015 Accepted: September 03, 2015 Published: September 16, 2015
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.
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