title: Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.
abstract: 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.
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA. manabu.kurokawa@dartmouth.edu
authors: Manabu
authors: M
authors: Kurokawa
authors: Takahiro
authors: T
authors: Ito
authors: Chih-Sheng
authors: CS
authors: Yang
authors: Chen
authors: C
authors: Zhao
authors: Andrew N
authors: AN
authors: Macintyre
authors: David A
authors: DA
authors: Rizzieri
authors: Jeffrey C
authors: JC
authors: Rathmell
authors: Michael W
authors: MW
authors: Deininger
authors: Tannishtha
authors: T
authors: Reya
authors: Sally
authors: S
authors: Kornbluth
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D020169:Caspases / Q000235:genetics* / Q000378:metabolism* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D014644:Genetic Variation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D015202:Protein Engineering; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D014161:Transduction, Genetic
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases