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[Cancer Research 65, 4500-4505, June 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

In vitro Activity of Bcr-Abl Inhibitors AMN107 and BMS-354825 against Clinically Relevant Imatinib-Resistant Abl Kinase Domain Mutants

Thomas O'Hare1, Denise K. Walters1, Eric P. Stoffregen2, Taiping Jia2, Paul W. Manley4, Jürgen Mestan4, Sandra W. Cowan-Jacob4, Francis Y. Lee5, Michael C. Heinrich3, Michael W.N. Deininger2 and Brian J. Druker1,2

1 Howard Hughes Medical Institute and 2 Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute; 3 Portland Veterans Affairs Medical Center, Portland, Oregon; 4 Novartis Institutes for Biomedical Research, Basel, Switzerland; and 5 Bristol-Myers Squibb Oncology, Princeton, New Jersey

Requests for reprints: Thomas O'Hare, Howard Hughes Medical Institute, Oregon Health and Science University, L592, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-5596; Fax: 503-494-3688; E-mail: oharet{at}ohsu.edu.

Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.




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D. A. Thomas
Philadelphia Chromosome Positive Acute Lymphocytic Leukemia: A New Era of Challenges
Hematology, January 1, 2007; 2007(1): 435 - 443.
[Abstract] [Full Text] [PDF]

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 ANN INTERN MEDHome page
H. M. Kantarjian, M. Talpaz, F. Giles, S. O'Brien, and J. Cortes
New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance
Ann Intern Med, December 19, 2006; 145(12): 913 - 923.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
F. R. Luo, Z. Yang, A. Camuso, R. Smykla, K. McGlinchey, K. Fager, C. Flefleh, S. Castaneda, I. Inigo, D. Kan, et al.
Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure
Clin. Cancer Res., December 1, 2006; 12(23): 7180 - 7186.
[Abstract] [Full Text] [PDF]

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 JCOHome page
S. Soverini, G. Martinelli, S. Colarossi, A. Gnani, F. Castagnetti, G. Rosti, C. Bosi, S. Paolini, M. Rondoni, P. P. Piccaluga, et al.
Presence or the Emergence of a F317L BCR-ABL Mutation May Be Associated With Resistance to Dasatinib in Philadelphia Chromosome Positive Leukemia
J. Clin. Oncol., November 20, 2006; 24(33): e51 - e52.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
W. Fiskus, M. Pranpat, M. Balasis, P. Bali, V. Estrella, S. Kumaraswamy, R. Rao, K. Rocha, B. Herger, F. Lee, et al.
Cotreatment with Vorinostat (Suberoylanilide Hydroxamic Acid) Enhances Activity of Dasatinib (BMS-354825) against Imatinib Mesylate-Sensitive or Imatinib Mesylate-Resistant Chronic Myelogenous Leukemia Cells.
Clin. Cancer Res., October 1, 2006; 12(19): 5869 - 5878.
[Abstract] [Full Text] [PDF]

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 BloodHome page
H. A. Bradeen, C. A. Eide, T. O'Hare, K. J. Johnson, S. G. Willis, F. Y. Lee, B. J. Druker, and M. W. Deininger
Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations
Blood, October 1, 2006; 108(7): 2332 - 2338.
[Abstract] [Full Text] [PDF]

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 BloodHome page
M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al.
Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet
Blood, September 15, 2006; 108(6): 1809 - 1820.
[Abstract] [Full Text] [PDF]

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 BloodHome page
E. Jabbour, J. Cortes, H. M. Kantarjian, S. Giralt, D. Jones, R. Jones, F. Giles, B. S. Andersson, R. Champlin, and M. de Lima
Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure
Blood, August 15, 2006; 108(4): 1421 - 1423.
[Abstract] [Full Text] [PDF]

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 BloodHome page
N. von Bubnoff, P. W. Manley, J. Mestan, J. Sanger, C. Peschel, and J. Duyster
Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107)
Blood, August 15, 2006; 108(4): 1328 - 1333.
[Abstract] [Full Text] [PDF]

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 BloodHome page
G. Ferrari-Amorotti, K. Keeshan, M. Zattoni, C. Guerzoni, G. Iotti, S. Cattelani, N. J. Donato, and B. Calabretta
Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP{alpha}
Blood, August 15, 2006; 108(4): 1353 - 1362.
[Abstract] [Full Text] [PDF]

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 BloodHome page
W. Fiskus, M. Pranpat, P. Bali, M. Balasis, S. Kumaraswamy, S. Boyapalle, K. Rocha, J. Wu, F. Giles, P. W. Manley, et al.
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells
Blood, July 15, 2006; 108(2): 645 - 652.
[Abstract] [Full Text] [PDF]

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 BloodHome page
D. L. White, V. A. Saunders, P. Dang, J. Engler, A. C. W. Zannettino, A. C. Cambareri, S. R. Quinn, P. W. Manley, and T. P. Hughes
OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib
Blood, July 15, 2006; 108(2): 697 - 704.
[Abstract] [Full Text] [PDF]

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 Mayo Clin Proc.Home page
A. Quintas-Cardama and J. E. Cortes
Chronic Myeloid Leukemia: Diagnosis and Treatment
Mayo Clin. Proc., July 1, 2006; 81(7): 973 - 988.
[Abstract] [Full Text] [PDF]

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 BloodHome page
N. P. Shah, F. Y. Lee, R. Luo, Y. Jiang, M. Donker, and C. Akin
Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis
Blood, July 1, 2006; 108(1): 286 - 291.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
M. Talpaz, N. P. Shah, H. Kantarjian, N. Donato, J. Nicoll, R. Paquette, J. Cortes, S. O'Brien, C. Nicaise, E. Bleickardt, et al.
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.
N. Engl. J. Med., June 15, 2006; 354(24): 2531 - 2541.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
H. Kantarjian, F. Giles, L. Wunderle, K. Bhalla, S. O'Brien, B. Wassmann, C. Tanaka, P. Manley, P. Rae, W. Mietlowski, et al.
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.
N. Engl. J. Med., June 15, 2006; 354(24): 2542 - 2551.
[Abstract] [Full Text] [PDF]

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 BloodHome page
E. Abruzzese, G. Del Poeta, R. Barbato, S. Fratoni, M. M. Trawinska, D. Zangrilli, A. M. Coletta, I. M. Patroi, F. Francesconi, G. Santeusanio, et al.
Complete regression of cutaneous lesions of refractory Ph+ ALL after 4 weeks of treatment with BMS-354825.
Blood, June 1, 2006; 107(11): 4571 - 4572.
[Full Text] [PDF]

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 Mol. Pharmacol.Home page
Z. Chen, F. Y. Lee, K. N. Bhalla, and J. Wu
Potent Inhibition of Platelet-Derived Growth Factor-Induced Responses in Vascular Smooth Muscle Cells by BMS-354825 (Dasatinib)
Mol. Pharmacol., May 1, 2006; 69(5): 1527 - 1533.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
Z. Zhang and K. E. Meier
New Assignments for Multitasking Signal Transduction Inhibitors
Mol. Pharmacol., May 1, 2006; 69(5): 1510 - 1512.
[Abstract] [Full Text] [PDF]

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 aacredbookHome page
K. Bhalla
Overview and Cytoplasmic Targets of HDAC Inhibitors
Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 309 - 312.
[Full Text] [PDF]

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 Mayo Clin Proc.Home page
M. J. Mauro and R. T. Maziarz
Stem Cell Transplantation in Patients With Chronic Myelogenous Leukemia: When Should It Be Used?
Mayo Clin. Proc., March 1, 2006; 81(3): 404 - 416.
[Abstract] [Full Text] [PDF]

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 ASH Education BookHome page
M. J. Mauro
Defining and Managing Imatinib Resistance
Hematology, January 1, 2006; 2006(1): 219 - 225.
[Abstract] [Full Text] [PDF]

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 BloodHome page
S. Kimura, H. Naito, H. Segawa, J. Kuroda, T. Yuasa, K. Sato, A. Yokota, Y. Kamitsuji, E. Kawata, E. Ashihara, et al.
NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia
Blood, December 1, 2005; 106(12): 3948 - 3954.
[Abstract] [Full Text] [PDF]

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 ASH ANNUAL MEETING ABSTRACTSHome page
C. L. Sawyers, H. Kantarjian, N. Shah, J. Cortes, R. Paquette, N. Donato, J. Nicoll, E. Bleickardt, T.-T. Chen, and M. Talpaz
Dasatinib (BMS-354825) in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Who Are Resistant or Intolerant to Imatinib: Update of a Phase I Study.
Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 38 - 38.
[Abstract]

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 ASH ANNUAL MEETING ABSTRACTSHome page
M. Copland, A. Hamilton, J. W. Baird, M. Barow, E. K. Allan, L. J. Elrick, and T. L. Holyoake
Dasatinib (BMS-354825) Has Increased Activity Against Bcr-Abl Compared to Imatinib in Primary CML Cells In Vitro, but Does Not Eradicate Quiescent CML Stem Cells.
Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 695 - 695.
[Abstract]

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 ASH ANNUAL MEETING ABSTRACTSHome page
F. Y. Lee, M.-L. Wen, R. Bhide, A. Camuso, S. Castenada, K. Fager, C. Flefleh, I. Inigo, D. Kan, R. Luo, et al.
Dasatinib (BMS-354825) Overcomes Multiple Mechanisms of Imatinib Resistance in Chronic Myeloid Leukemia (CML).
Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 1994 - 1994.
[Abstract]

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 ASH ANNUAL MEETING ABSTRACTSHome page
C. Peng, Y. Hu, F. Y. Lee, and S. Li
Targeting Chronic Myeloid Leukemia (CML) Stem Cells by BMS-214662 in Mice.
Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 2861 - 2861.
[Abstract]

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 ASH Education BookHome page
N. P. Shah
Loss of Response to Imatinib: Mechanisms and Management
Hematology, January 1, 2005; 2005(1): 183 - 187.
[Abstract] [Full Text] [PDF]

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 ASH Education BookHome page
R. L. Ilaria Jr.
Pathobiology of Lymphoid and Myeloid Blast Crisis and Management Issues
Hematology, January 1, 2005; 2005(1): 188 - 194.
[Abstract] [Full Text] [PDF]


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