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

Stefano Iacovelli, Maria Rosaria Ricciardi, Matteo Allegretti, Simone Mirabilii, Roberto Licchetta, Paola Bergamo, Cinzia Rinaldo, Ann Zeuner, Robin Foà, Michele Milella, James A. McCubrey, Alberto M. Martelli, Agostino Tafuri

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)32089-32103
Number of pages15
JournalOncotarget
Volume6
Issue number31
DOIs
Publication statusPublished - 2015

Fingerprint

Precursor Cell Lymphoblastic Leukemia-Lymphoma
Apoptosis
TOR Serine-Threonine Kinases
Proteasome Endopeptidase Complex
ABT-737
Phosphatidylinositol 3-Kinases
Proteins
Down-Regulation
Pharmaceutical Preparations

Keywords

  • Acute lymphoblastic leukemia
  • BH3 mimetic resistance
  • Mcl-1
  • MTOR inhibition
  • Targeted therapies

ASJC Scopus subject areas

  • Oncology

Cite this

Iacovelli, S., Ricciardi, M. R., Allegretti, M., Mirabilii, S., Licchetta, R., Bergamo, P., ... Tafuri, A. (2015). Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. Oncotarget, 6(31), 32089-32103. https://doi.org/10.18632/oncotarget.5156

Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. / Iacovelli, Stefano; Ricciardi, Maria Rosaria; Allegretti, Matteo; Mirabilii, Simone; Licchetta, Roberto; Bergamo, Paola; Rinaldo, Cinzia; Zeuner, Ann; Foà, Robin; Milella, Michele; McCubrey, James A.; Martelli, Alberto M.; Tafuri, Agostino.

In: Oncotarget, Vol. 6, No. 31, 2015, p. 32089-32103.

Research output: Contribution to journalArticle

Iacovelli, S, Ricciardi, MR, Allegretti, M, Mirabilii, S, Licchetta, R, Bergamo, P, Rinaldo, C, Zeuner, A, Foà, R, Milella, M, McCubrey, JA, Martelli, AM & Tafuri, A 2015, 'Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia', Oncotarget, vol. 6, no. 31, pp. 32089-32103. https://doi.org/10.18632/oncotarget.5156
Iacovelli, Stefano ; Ricciardi, Maria Rosaria ; Allegretti, Matteo ; Mirabilii, Simone ; Licchetta, Roberto ; Bergamo, Paola ; Rinaldo, Cinzia ; Zeuner, Ann ; Foà, Robin ; Milella, Michele ; McCubrey, James A. ; Martelli, Alberto M. ; Tafuri, Agostino. / Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia. In: Oncotarget. 2015 ; Vol. 6, No. 31. pp. 32089-32103.
@article{c92f3c357d5b46a8aaaf6146f3b0e232,
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.",
keywords = "Acute lymphoblastic leukemia, BH3 mimetic resistance, Mcl-1, MTOR inhibition, Targeted therapies",
author = "Stefano Iacovelli and Ricciardi, {Maria Rosaria} and Matteo Allegretti and Simone Mirabilii and Roberto Licchetta and Paola Bergamo and Cinzia Rinaldo and Ann Zeuner and Robin Fo{\`a} and Michele Milella and McCubrey, {James A.} and Martelli, {Alberto M.} and Agostino Tafuri",
year = "2015",
doi = "10.18632/oncotarget.5156",
language = "English",
volume = "6",
pages = "32089--32103",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "31",

}

TY - JOUR

T1 - Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia

AU - Iacovelli, Stefano

AU - Ricciardi, Maria Rosaria

AU - Allegretti, Matteo

AU - Mirabilii, Simone

AU - Licchetta, Roberto

AU - Bergamo, Paola

AU - Rinaldo, Cinzia

AU - Zeuner, Ann

AU - Foà, Robin

AU - Milella, Michele

AU - McCubrey, James A.

AU - Martelli, Alberto M.

AU - Tafuri, Agostino

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Acute lymphoblastic leukemia

KW - BH3 mimetic resistance

KW - Mcl-1

KW - MTOR inhibition

KW - Targeted therapies

UR - http://www.scopus.com/inward/record.url?scp=84945563414&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945563414&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.5156

DO - 10.18632/oncotarget.5156

M3 - Article

VL - 6

SP - 32089

EP - 32103

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 31

ER -