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Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
Neil P. Shah,1Chris Tran,1,2Francis Y. Lee,3Ping Chen,3Derek Norris,3Charles L. Sawyers1,2*
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec)in chronic myeloid leukemia (CML) occurs through selection fortumor cells harboring BCR-ABL kinase domain point mutationsthat interfere with drug binding. Crystallographic studies predictthat most imatinib-resistant mutants should remain sensitiveto inhibitors that bind ABL with less stringent conformationalrequirements. BMS-354825 is an orally bioavailable ABL kinaseinhibitor with two-log increased potency relative to imatinibthat retains activity against 14 of 15 imatinib-resistant BCR-ABLmutants. BMS-354825 prolongs survival of mice with BCR-ABL–drivendisease and inhibits proliferation of BCR-ABL–positivebone marrow progenitor cells from patients with imatinib-sensitiveand imatinib-resistant CML. These data illustrate how molecularinsight into kinase inhibitor resistance can guide the designof 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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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
|Abstract »|Full Text »|PDF »
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
|Abstract »|Full Text »|PDF »
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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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
|Abstract »|Full Text »|PDF »
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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