title: SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib.
abstract: 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.
authors: Division of Hematology and Medical Oncology, Oregon Health & Science University Cancer Institute, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors: Thomas
authors: T
authors: O'Hare
authors: Christopher A
authors: CA
authors: Eide
authors: Jeffrey W
authors: JW
authors: Tyner
authors: Amie S
authors: AS
authors: Corbin
authors: Matthew J
authors: MJ
authors: Wong
authors: Sean
authors: S
authors: Buchanan
authors: Kevin
authors: K
authors: Holme
authors: Katayoun A
authors: KA
authors: Jessen
authors: Crystal
authors: C
authors: Tang
authors: Hal A
authors: HA
authors: Lewis
authors: Richard D
authors: RD
authors: Romero
authors: Stephen K
authors: SK
authors: Burley
authors: Michael W
authors: MW
authors: Deininger
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib