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Science 16 July 2004:
Vol. 305. no. 5682, pp. 399 - 401
DOI: 10.1126/science.1099480
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Reports

Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor

Neil P. Shah,1 Chris Tran,1,2 Francis Y. Lee,3 Ping Chen,3 Derek Norris,3 Charles L. Sawyers1,2*

Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL–driven disease and inhibits proliferation of BCR-ABL–positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.

1 Division of Hematology and Oncology, Department of Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
2 Howard Hughes Medical Institute, The David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
3 Bristol-Myers Squibb Oncology, Princeton, NJ, USA.

* To whom correspondence should be addressed. E-mail: csawyers{at}mednet.ucla.edu

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Blood 110, 2309-2315
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Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.
T. O'Hare, C. A. Eide, and M. W. N. Deininger (2007)
Blood 110, 2242-2249
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Progressive Thoughts about Progressive Disease.
N. P. Shah (2007)
Clin. Cancer Res. 13, 5229-5231
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Pleural Effusion in Patients With Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure.
A. Quintas-Cardama, H. Kantarjian, S. O'Brien, G. Borthakur, J. Bruzzi, R. Munden, and J. Cortes (2007)
J. Clin. Oncol. 25, 3908-3914
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Sorafenib Inhibits the Imatinib-Resistant KITT670I Gatekeeper Mutation in Gastrointestinal Stromal Tumor.
T. Guo, N. P. Agaram, G. C. Wong, G. Hom, D. D'Adamo, R. G. Maki, G. K. Schwartz, D. Veach, B. D. Clarkson, S. Singer, et al. (2007)
Clin. Cancer Res. 13, 4874-4881
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The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib.
O. Hantschel, U. Rix, U. Schmidt, T. Burckstummer, M. Kneidinger, G. Schutze, J. Colinge, K. L. Bennett, W. Ellmeier, P. Valent, et al. (2007)
PNAS 104, 13283-13288
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Oncogenic Activity of Epidermal Growth Factor Receptor Kinase Mutant Alleles Is Enhanced by the T790M Drug Resistance Mutation.
N. Godin-Heymann, I. Bryant, M. N. Rivera, L. Ulkus, D. W. Bell, D. J. Riese II, J. Settleman, and D. A. Haber (2007)
Cancer Res. 67, 7319-7326
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Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells.
C. Peng, J. Brain, Y. Hu, A. Goodrich, L. Kong, D. Grayzel, R. Pak, M. Read, and S. Li (2007)
Blood 110, 678-685
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Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).
H. Pfeifer, B. Wassmann, A. Pavlova, L. Wunderle, J. Oldenburg, A. Binckebanck, T. Lange, A. Hochhaus, S. Wystub, P. Bruck, et al. (2007)
Blood 110, 727-734
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Inhibition of the T790M Gatekeeper Mutant of the Epidermal Growth Factor Receptor by EXEL-7647.
S. B. Gendreau, R. Ventura, P. Keast, A. D. Laird, F. M. Yakes, W. Zhang, F. Bentzien, B. Cancilla, J. Lutman, F. Chu, et al. (2007)
Clin. Cancer Res. 13, 3713-3723
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Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial.
H. Kantarjian, R. Pasquini, N. Hamerschlak, P. Rousselot, J. Holowiecki, S. Jootar, T. Robak, N. Khoroshko, T. Masszi, A. Skotnicki, et al. (2007)
Blood 109, 5143-5150
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Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure.
A. Fabarius, C. Haferlach, M. C. Muller, P. Erben, T. Lahaye, M. Giehl, O. Frank, W. Seifarth, R. Hehlmann, and A. Hochhaus (2007)
Haematologica 92, 834-837
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Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor {beta} Gatekeeper Mutants.
T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro, and F. Carlomagno (2007)
Clin. Cancer Res. 13, 3363-3369
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Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase.
F. Guilhot, J. Apperley, D.-W. Kim, E. O. Bullorsky, M. Baccarani, G. J. Roboz, S. Amadori, C. A. de Souza, J. H. Lipton, A. Hochhaus, et al. (2007)
Blood 109, 4143-4150
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Instability of BCR-ABL Gene in Primary and Cultured Chronic Myeloid Leukemia Stem Cells.
X. Jiang, K. M. Saw, A. Eaves, and C. Eaves (2007)
J Natl Cancer Inst 99, 680-693
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MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant (2007)
Blood 109, 4006-4015
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Unraveling CML phase by phase.
J. Goldman (2007)
Blood 109, 3128
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Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis.
J. Cortes, P. Rousselot, D.-W. Kim, E. Ritchie, N. Hamerschlak, S. Coutre, A. Hochhaus, F. Guilhot, G. Saglio, J. Apperley, et al. (2007)
Blood 109, 3207-3213
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