A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia

• Published in: Leukemia Vol. 29; no. 8; pp. 1668 - 1675
• Main Authors: Woessner, D W, Eiring, A M, Bruno, B J, Zabriskie, M S, Reynolds, K R, Miller, G D, O'Hare, T, Deininger, M W, Lim, C S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2015; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/31; 14; 14/35; 38/35; 42; 45; 631/208/737; 631/67/1990/283/1896; 631/80/82/23; 692/699/67/1059/602; 82; 82/80; Apoptosis; Cancer Research; Care and treatment; CD34 antigen; Cell Proliferation; Chronic myeloid leukemia; Critical Care Medicine; Development and progression; Dimerization; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug targeting; Drug therapy; Fusion Proteins, bcr-abl - chemistry; Fusion Proteins, bcr-abl - genetics; Gene mutations; Genetic aspects; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Medicine; Medicine & Public Health; Methods; Molecular targeted therapy; Mutants; Mutation; Mutation (Biology); Myeloid leukemia; Oligomerization; Oncology; original-article; Phosphorylation; Point Mutation - genetics; Protein Kinase Inhibitors - pharmacology; Protein Multimerization - genetics; Protein Structure, Tertiary; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Tumor Cells, Cultured; Tumor Stem Cell Assay; Tyrosine; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.53

Targeted therapy of chronic myeloid leukemia (CML) is currently based on small-molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CC mut3 , which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CC mut3 exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CC mut3 inhibits colony formation by primary CML CD34 + cells ex vivo , including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies.