Targeting 14-3-3 sensitizes native and mutant BCR-ABL to inhibition with U0126, rapamycin and Bcl-2 inhibitor GX15-070

Leukemia. 2008 Mar;22(3):572-7. doi: 10.1038/sj.leu.2405064. Epub 2007 Dec 13.

Abstract

Small molecule tyrosine kinase inhibitors, such as imatinib, are effective therapies for BCR-ABL-mediated human leukemias. However, clinical drug resistance occurs, which warrants development of alternative and/or complementary therapeutic strategies to target critical downstream signaling molecules. We recently demonstrated that disrupting 14-3-3/ligand association by a peptide-based 14-3-3 competitive antagonist R18 induces significant apoptosis, partially through reactivation of AKT-inhibited proapoptotic FOXO3a, in FGFR1 fusion-transformed hematopoietic cells. Here, we report that targeting 14-3-3 by R18 effectively induced significant apoptosis in Ba/F3 and K562 cells expressing BCR-ABL, similarly through liberation and reactivation of FOXO3a. Moreover, R18 sensitized BCR-ABL-transformed cells to inhibition with MEK1 inhibitor U0126, Bcl-2 inhibitor GX15-070, or mTOR inhibitor rapamycin. Treatment with these reagents potentiated R18-induced reactivation of proapoptotic FOXO3a with enhanced expression of downstream transcription targets p27(kip1) and Bim1. Furthermore, R18-induced apoptotic cell death in cells expressing diverse imatinib-resistant BCR-ABL mutants, including T315I. This inhibition was enhanced by R18 in combination with U0126 and rapamycin. Thus, our findings suggest that targeting 14-3-3 may potentiate the effects of conventional therapy for BCR-ABL-associated hematopoietic malignancies, and overcome drug resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / antagonists & inhibitors*
  • Amino Acid Sequence
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides
  • Butadienes / pharmacology*
  • Drug Resistance, Neoplasm / genetics
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / physiology
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Imatinib Mesylate
  • Intracellular Signaling Peptides and Proteins
  • K562 Cells / drug effects
  • K562 Cells / enzymology
  • Molecular Sequence Data
  • Mutation, Missense
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • Nitriles / pharmacology*
  • Peptides / genetics
  • Peptides / pharmacology*
  • Piperazines / pharmacology
  • Point Mutation
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology*
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology*

Substances

  • 14-3-3 Proteins
  • Antineoplastic Agents
  • Benzamides
  • Butadienes
  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • Nitriles
  • Peptides
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • R18 peptide
  • Recombinant Fusion Proteins
  • U 0126
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • obatoclax
  • Sirolimus