Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.

Kurokawa, Manabu

Ito, Takahiro

Yang, Chih-Sheng

Zhao, Chen

Macintyre, Andrew N

Rizzieri, David A

Rathmell, Jeffrey C

Deininger, Michael W

Reya, Tannishtha

Kornbluth, Sally

United States

2014-03-06T17:28:25Z

2013-02-05

Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.

http://www.ncbi.nlm.nih.gov/pubmed/23324740

1206551110

1091-6490

https://hdl.handle.net/10161/8388

eng

Proceedings of the National Academy of Sciences

Proc Natl Acad Sci U S A

10.1073/pnas.1206551110

Animals

Antineoplastic Agents

Apoptosis

Benzamides

Caspase 8

Caspases

Drug Resistance, Neoplasm

Enzyme Activation

Fusion Proteins, bcr-abl

Genetic Variation

Hematopoietic Stem Cells

Humans

Imatinib Mesylate

K562 Cells

Leukemia

Mice

Piperazines

Protein Engineering

Protein Kinase Inhibitors

Pyrimidines

Recombinant Proteins

Transduction, Genetic

Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.

Journal article

Macintyre, Andrew N|0000-0002-5297-0207

http://www.ncbi.nlm.nih.gov/pubmed/23324740

2300

2305

6

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Duke Molecular Physiology Institute

Institutes and Centers

Medicine

Medicine, Cellular Therapy

Pharmacology & Cancer Biology

Sarah Stedman Nutrition & Metabolism Center

School of Medicine

Published

110