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

Oncotarget. 2015 Oct 13;6(31):32089-103. doi: 10.18632/oncotarget.5156.

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: BH3 mimetic resistance; Mcl-1; acute lymphoblastic leukemia; mTOR inhibition; targeted therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Biomimetics
  • Biphenyl Compounds / pharmacology
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Child
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism*
  • Female
  • Humans
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Nitrophenols / pharmacology
  • Peptide Fragments / pharmacology*
  • Piperazines / pharmacology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Proto-Oncogene Proteins / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • Sulfonamides / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured

Substances

  • ABT-737
  • Antineoplastic Agents
  • Bax protein (53-86)
  • Biphenyl Compounds
  • MCL1 protein, human
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitrophenols
  • Peptide Fragments
  • Piperazines
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • temsirolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus