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.
journal_name
Proc Natl Acad Sci U S Aauthors
Kurokawa M,Ito T,Yang CS,Zhao C,Macintyre AN,Rizzieri DA,Rathmell JC,Deininger MW,Reya T,Kornbluth Sdoi
10.1073/pnas.1206551110subject
Has Abstractpub_date
2013-02-05 00:00:00pages
2300-5issue
6eissn
0027-8424issn
1091-6490pii
1206551110journal_volume
110pub_type
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