Editors' ChoiceCancer Biology

The Appearance of Drug Resistance

Science's STKE  07 Aug 2001:
Vol. 2001, Issue 94, pp. tw15
DOI: 10.1126/stke.2001.94.tw15

STI-571 is a new cancer drug that has shown remarkable efficacy in patients who are in the early stages of chronic myeloid leukemia (CML). The drug inhibits the Abl kinase, which is constitutively activated in CML patients, because they carry a characteristic chromosomal translocation that fuses the ABL gene with the unrelated BCR gene. Patients in whom CML has progressed to a stage called blast crisis respond to STI-571 initially, but then develop resistance. Gorre et al. studied nine patients who had relapsed after STI-571 treatment and found that all nine showed reactivation of the Bcr-Abl signaling pathway. Six patients had acquired the same amino acid substitution in the Abl kinase domain--a change predicted to alter interaction of the kinase with the drug--and the other three showed BCR-ABL gene amplification. Identification of the mechanisms responsible for STI-571 resistance may facilitate the design of next-generation drugs for CML. (See the 22 June news story by Marx.)

M. E. Gorre, M. Mohammed, K. Ellwood, N. Hsu, R. Paquette, P. N. Rao, C. L. Sawyers, Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876-880 (2001). [Abstract] [Full Text]

J. Marx, Why some leukemia cells resist STI-571. Science 292, 2231-2233 (2001). [Full Text]

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