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Science 305 (5682): 399-401

Copyright © 2004 by the American Association for the Advancement of Science

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*

Abstract: 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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Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors.
S. Soverini, A. Gnani, S. Colarossi, F. Castagnetti, E. Abruzzese, S. Paolini, S. Merante, E. Orlandi, S. de Matteis, A. Gozzini, et al. (2009)
Blood 114, 2168-2171
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Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients.
K. V. Lu, S. Zhu, A. Cvrljevic, T. T. Huang, S. Sarkaria, D. Ahkavan, J. Dang, E. B. Dinca, S. B. Plaisier, I. Oderberg, et al. (2009)
Cancer Res. 69, 6889-6898
   Abstract »    Full Text »    PDF »
The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo.
M.-P. Gratacap, V. Martin, M.-C. Valera, S. Allart, C. Garcia, P. Sie, C. Recher, and B. Payrastre (2009)
Blood 114, 1884-1892
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Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors.
Z. Jagani, K. Song, J. L. Kutok, M. R. Dewar, A. Melet, T. Santos, A. Grassian, S. Ghaffari, C. Wu, R. Ren, et al. (2009)
Cancer Res. 69, 6546-6555
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Kinome Profiling of Chondrosarcoma Reveals Src-Pathway Activity and Dasatinib as Option for Treatment.
Y. M. Schrage, I. H. Briaire-de Bruijn, N. F.C.C. de Miranda, J. van Oosterwijk, A. H.M. Taminiau, T. van Wezel, P. C.W. Hogendoorn, and J. V.M.G. Bovee (2009)
Cancer Res. 69, 6216-6222
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Dasatinib in the Treatment of Chronic Myeloid Leukemia in Accelerated Phase After Imatinib Failure: The START A Trial.
J. F. Apperley, J. E. Cortes, D.-W. Kim, L. Roy, G. J. Roboz, G. Rosti, E. O. Bullorsky, E. Abruzzese, A. Hochhaus, D. Heim, et al. (2009)
J. Clin. Oncol. 27, 3472-3479
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Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up.
H. Kantarjian, J. Cortes, D.-W. Kim, P. Dorlhiac-Llacer, R. Pasquini, J. DiPersio, M. C. Muller, J. P. Radich, H. J. Khoury, N. Khoroshko, et al. (2009)
Blood 113, 6322-6329
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Discovery and Exploitation of Inhibitor-resistant Aurora and Polo Kinase Mutants for the Analysis of Mitotic Networks.
P. J. Scutt, M. L. H. Chu, D. A. Sloane, M. Cherry, C. R. Bignell, D. H. Williams, and P. A. Eyers (2009)
J. Biol. Chem. 284, 15880-15893
   Abstract »    Full Text »    PDF »
Combination Therapies against Chronic Myeloid Leukemia: Short-term versus Long-term Strategies.
N. L. Komarova and D. Wodarz (2009)
Cancer Res. 69, 4904-4910
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Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells.
E. Kennah, A. Ringrose, L. L. Zhou, S. Esmailzadeh, H. Qian, M.-w. Su, Y. Zhou, and X. Jiang (2009)
Blood 113, 4646-4655
   Abstract »    Full Text »    PDF »
Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia.
T. Tyler (2009)
Annals of Pharmacotherapy 43, 920-927
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FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro.
N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. Peschel, and J. Duyster (2009)
Cancer Res. 69, 3032-3041
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Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment.
J. S. Lagas, R. A.B. van Waterschoot, V. A.C.J. van Tilburg, M. J. Hillebrand, N. Lankheet, H. Rosing, J. H. Beijnen, and A. H. Schinkel (2009)
Clin. Cancer Res. 15, 2344-2351
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Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations.
M. A. Seeliger, P. Ranjitkar, C. Kasap, Y. Shan, D. E. Shaw, N. P. Shah, J. Kuriyan, and D. J. Maly (2009)
Cancer Res. 69, 2384-2392
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