Targeting 14-3-3 sensitizes native and mutant BCR-ABL to inhibition with U0126, rapamycin and Bcl-2 inhibitor GX15-070.
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.
Dong
S
S
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kang
S
S
Lonial
S
S
Khoury
H J
HJ
Viallet
J
J
Chen
J
J
D048948:14-3-3 Proteins / Q000037:antagonists & inhibitors*; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002070:Butadienes / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells / Q000187:drug effects / Q000201:enzymology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D001549:Benzamides; D002070:Butadienes; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009570:Nitriles; D010455:Peptides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527524:R18 peptide; D011993:Recombinant Fusion Proteins; C113580:U 0126; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C520962:obatoclax; D020123:Sirolimus