Glivec Research Today is a free monthly online journal that collates and summarizes the latest research about Glivec, including details on gleevec, imatinib, cancer, treatment, side-effects.

SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib.

O'Hare T, Eide CA, Tyner JW, Corbin AS, Wong MJ, Buchanan S, Holme K, Jessen KA, Tang C, Lewis HA, Romero RD, Burley SK, Deininger MW

Division of Hematology and Medical Oncology, Oregon Health & Science University Cancer Institute, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.

Imatinib inhibits Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The second-line inhibitors nilotinib and dasatinib are effective in patients with imatinib resistance resulting from Bcr-Abl kinase domain mutations. Bcr-Abl(T315I), however, is resistant to all Abl kinase inhibitors in clinical use and is emerging as the most frequent cause of salvage therapy failure. SGX393 is a potent inhibitor of native and T315I-mutant Bcr-Abl kinase that blocks the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-Abl(T315I), with minimal toxicity against Bcr-Abl-negative cell lines or normal bone marrow. A screen for Bcr-Abl mutants emerging in the presence of SGX393 revealed concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted emergence of resistant subclones, including Bcr-Abl(T315I). These findings suggest that combination of a T315I inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia.

Published 9 April 2008 in Proc Natl Acad Sci U S A, 105(14): 5507-12.
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