Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Matteo Allegretti (Creator)

Paola Bergamo (Creator)

Robin Foà (Creator)

Stefano Iacovelli (Creator)

Roberto Licchetta (Creator)

Alberto M. Martelli (Creator)

James A. McCubrey (Creator)

Michele Milella (Creator)

Simone Mirabilii (Creator)

Maria Rosaria Ricciardi (Creator)

Cinzia Rinaldo (Creator)

Agostino Tafuri (Creator)

Ann Zeuner (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Helping Hands Guidebook; 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.

Additional Information

Publication

Other

Oncotarget; 6:31 p. 32089-32103

Language: English

Date: 2015

Keywords

mTOR inhibition, acute lymphoblastic leukemia, targeted therapies, Mcl-1, BH3 mimetic resistance

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