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Blood, 15 January 2007, Vol. 109, No. 2, pp. 396-397. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Martinelli, G. Articles by Baccarani, M. Search for Related Content PubMed Articles by Martinelli, G. Articles by Baccarani, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Comment on Giles et al, page 500 MK-0457: a light at the end of the tunnel? Giovanni Martinelli, Simona Soverini, Ilaria Iacobucci, and Michele Baccarani UNIVERITY OF BOLOGNA In this issue of Blood, Giles and colleagues report the remarkable clinical activity of MK-0457, an aurora kinase inhibitor, in 3 Philadelphia chromosome–positive leukemia patients harboring the highly resistant T315I mutation. To counteract the problem of imatinib resistance due to BCR-ABL gene mutations in Philadelphia chromosome–positive (Ph+) leukemias, several new drugs have been tested in preclinical assays, and 3 of them are currently in clinical development: the dual-specificity Src/Abl inhibitors dasatinib         (BMS354825) and SKI606, and the imatinib derivative nilotinib (AMN-107). Nevertheless, the T315I mutant has remained an Achilles heel for at least 2 of these second-generation inhibitors (ie, nilotinib and dasatinib).1,2 Structural analyses predict that the T315I eliminates a crucial hydrogen bond required for high-affinity binding of imatinib, dasatinib, and nilotinib, and alters adversely the topology of the ATP-binding pocket.3 In this issue of Blood, Giles and colleagues document for the first time the efficacy of a tyrosine kinase inhibitor in T315I-positive patients—2 patients with chronic myeloid leukemia (CML) in accelerated phase and a patient with Ph+ acute lymphoblastic leukemia (ALL), resistant both to imatinib and to dasatinib or nilotinib, who received MK-0457 within a phase 1/2 study. All 3 patients achieved clinical responses to doses that were not associated with adverse events. The use of this aurora kinase inhibitor in the treatment of Ph+ leukemias found its rationale in the results of a recent screening4 of existing chemical compounds for their ability to bind and inhibit drug-resistant mutant variants of Bcr-Abl, including the T315I. The study revealed that MK-0457 binds T315I Bcr-Abl with very high affinity (Kd = 5 nM). Subsequent cocrystal studies showed that MK-0457 binds Bcr-Abl in a mode that accommodates the substitution of the bulkier isoleucine for threonine at residue 315 (see figure), and for this reason effectively inhibits the kinase activity of both wild-type and T315I Bcr-Abl in vitro at micromolar concentrations.5 Despite the small number of T315I-positive patients treated with MK-0457 and the very short follow-up, the clinical observations of Giles and colleagues seem to fully validate this preclinical evidence. View larger version (60K): [in this window] [in a new window]   Possible explanation for MK-0457 activity in T315I Bcr-Abl–positive CML and Ph+ ALL. (A) MK-0457 has been shown to be less deeply buried in the Abl kinase domain (right) with respect to imatinib (left). As a consequence, (B) a close encounter with threonine 315 is avoided, explaining the ability of MK-0457 to accommodate easily the substitution of threonine with isoleucine. Modified, with permission, from Young et al5.   If, on one hand, results of crystallographic and in vitro studies made it reasonable to assess this compound in Ph+ leukemia patients, the inhibition of aurora kinases by MK-0457 raises the question whether these targets may also harbor some pathogenetic role in CML and/or Ph+ ALL. Aurora kinases regulate diverse cell-cycle events, ranging from the entry into mitosis, centrosome function, mitotic spindle formation, and chromosome orientation to segregation. Aberrant activity of these kinases has been reported in many human tumors, but it is yet unclear whether, in T315I Bcr-Abl–positive CML and Ph+ ALL, there is a selective deregulation of aurora kinases and if auroras may be a suitable secondary target for inhibition. Whatever the actual mechanism of action of MK-0457 is, the observations of Giles et al may set the stage for a breakthrough in the management of patients with the T315I mutation, who are at present without an effective treatment, if we exclude allogeneic stem cell transplantation. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. References Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354:2531–2541.[Abstract/Free Full Text] Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354:2542–2551.[Abstract/Free Full Text] Pricl S, Fermeglia M, Ferrone M, et al. T315I-mutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational study. Mol Cancer Ther 2005; 4:1167–1174.[Abstract/Free Full Text] Carter TA, Wodicka LM, Shah NP, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 2005; 102:11011–11016.[Abstract/Free Full Text] Young MA, Shah NP, Chao LH, et al. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 2006; 66:1007–1014.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation Francis J. Giles, Jorge Cortes, Dan Jones, Donald Bergstrom, Hagop Kantarjian, and Steven J. Freedman Blood 2007 109: 500-502. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Martinelli, G. Articles by Baccarani, M. Search for Related Content PubMed Articles by Martinelli, G. Articles by Baccarani, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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