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

• Type of Material: Article
• Authors: S Dong, Emory University; S Kang, Emory University; Sagar Lonial, Emory University; H Jean Khoury, Emory University; J Viallet, Gemin X Biotechnologies Inc.; Jing Chen, Emory University
• Language: English
• Date: 2008-03
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2007, Rights Managed by Nature Publishing Group
• Final Published Version (URL): http://www.nature.com/leu/journal/v22/n3/full/2405064a.html
• Title of Journal or Parent Work: Leukemia
• ISSN: 0887-6924
• Volume: 22
• Issue: 3
• Start Page: 572
• End Page: 577
• Grant/Funding Information: This work was supported in part by NIH grant CA120272 (J Chen), the Leukemia and Lymphoma Society (J Chen) and the Golfer Against Cancer Foundation (J Chen and S Lonial).
• Keywords: chronic myelogenous leukemia (CML); BCR-ABL; peptide-based 14-3-3 antagonist R18; BCR-ABL imatinib-resistant mutations
• Research Categories: Health Sciences, Oncology; Health Sciences, General

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 p27kip1 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.