| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cancer Therapy: Preclinical |
Authors' Affiliations: 1 Howard Hughes Medical Institute, Oregon Health and Science University; 2 Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute; and 3 Portland Veterans Affairs Medical Center, Portland, Oregon
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.
Purpose: Chronic myeloid leukemia (CML) is effectively treated with imatinib. However, reactivation of Bcr-Abl via kinase domain mutations that reduce sensitivity to imatinib can cause relapse. As combination therapy is frequently used to prevent emergence of resistance, the combination of imatinib with an inhibitor of imatinib-resistant Bcr-Abl mutants (e.g., Src/Abl inhibitors AP23848 and BMS-354825) was investigated.
Experimental Design: To test this approach, cellular proliferation and Bcr-Abl tyrosine phosphorylation assays were done on Ba/F3 cells expressing wild-type (WT) Bcr-Abl and four common imatinib-resistant mutants (Y253F, E255K, T315I, and M351T). Colony-forming assays with primary CML cells were also done.
Results: Both Src/Abl inhibitors retained full inhibitory capacity when coadministered with imatinib at concentrations above typical clinical levels. For cells expressing WT Bcr-Abl or the marginally imatinib-resistant mutant M351T, inclusion of imatinib at therapeutic levels enhanced the effects of the Src/Abl inhibitors. By comparison, for the highly imatinib-resistant mutants Y253F and E255K, inclusion of imatinib at clinical levels resulted in only a slight enhancement beyond the effects of the Src/Abl inhibitors. None of the inhibitors affected Bcr-Abl T315I cells. Colony-forming assays with primary CML cells yielded analogous results.
Conclusions: Our results indicate that Src/Abl inhibitors are compatible with imatinib and suggest that combined Abl inhibitor therapy is a feasible treatment strategy for patients with CML.
This article has been cited by other articles:
|
|
 |
|
  H. Konig, M. Copland, S. Chu, R. Jove, T. L. Holyoake, and R. Bhatia Effects of Dasatinib on Src Kinase Activity and Downstream Intracellular Signaling in Primitive Chronic Myelogenous Leukemia Hematopoietic Cells Cancer Res., December 1, 2008; 68(23): 9624 - 9633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Akhmetshina, C. Dees, M. Pileckyte, B. Maurer, R. Axmann, A. Jungel, J. Zwerina, S. Gay, G. Schett, O. Distler, et al. Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis FASEB J, July 1, 2008; 22(7): 2214 - 2222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. O'Hare, C. A. Eide, J. W. Tyner, A. S. Corbin, M. J. Wong, S. Buchanan, K. Holme, K. A. Jessen, C. Tang, H. A. Lewis, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib PNAS, April 8, 2008; 105(14): 5507 - 5512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M Marshall and J. M Hammond Treatment Options in Imatinib-Resistant Chronic Myelogenous Leukemia Ann. Pharmacother., February 1, 2008; 42(2): 259 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Fizazi The role of Src in prostate cancer Ann. Onc., November 1, 2007; 18(11): 1765 - 1773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Pfeifer, B. Wassmann, A. Pavlova, L. Wunderle, J. Oldenburg, A. Binckebanck, T. Lange, A. Hochhaus, S. Wystub, P. Bruck, et al. 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) Blood, July 15, 2007; 110(2): 727 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kantarjian, R. Pasquini, N. Hamerschlak, P. Rousselot, J. Holowiecki, S. Jootar, T. Robak, N. Khoroshko, T. Masszi, A. Skotnicki, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial Blood, June 15, 2007; 109(12): 5143 - 5150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro, and F. Carlomagno Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor {beta} Gatekeeper Mutants Clin. Cancer Res., June 1, 2007; 13(11): 3363 - 3369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Blood, May 1, 2007; 109(9): 4006 - 4015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Weisberg, L. Catley, R. D. Wright, D. Moreno, L. Banerji, A. Ray, P. W. Manley, J. Mestan, D. Fabbro, J. Jiang, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias Blood, March 1, 2007; 109(5): 2112 - 2120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 C. A. Fausel Novel treatment strategies for chronic myeloid leukemia. Am. J. Health Syst. Pharm., December 1, 2006; 63(23_Supplement_8): S15 - S20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Druker Circumventing resistance to kinase-inhibitor therapy. N. Engl. J. Med., June 15, 2006; 354(24): 2594 - 2596. [Full Text] [PDF]
|
|
|
|
|
|
M. J. Mauro Defining and Managing Imatinib Resistance Hematology, January 1, 2006; 2006(1): 219 - 225. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
