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Originally published in Science Express on 21 June 2001
Science 3 August 2001:
Vol. 293. no. 5531, pp. 876 - 880
DOI: 10.1126/science.1062538
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Reports

Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification

Mercedes E. Gorre,13 Mansoor Mohammed,2 Katharine Ellwood,1 Nicholas Hsu,1 Ron Paquette,1 P. Nagesh Rao,2 Charles L. Sawyers13*

Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, we find that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined. In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance in a reconstitution experiment. In three patients, resistance was associated with progressive BCR-ABL gene amplification. These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance.

1 Department of Medicine,
2 Department of Pathology, and
3 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
*   To whom correspondence should be addressed. E-mail: csawyers{at}mednet.ucla.edu

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Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation.
F. E. Nicolini, S. Hayette, S. Corm, E. Bachy, D. Bories, M. Tulliez, F. Guilhot, L. Legros, F. Maloisel, J.-J. Kiladjian, et al. (2007)
Haematologica 92, 1238-1241
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Bcr-Abl-Independent Imatinib-Resistant K562 Cells Show Aberrant Protein Acetylation and Increased Sensitivity to Histone Deacetylase Inhibitors.
S. M. Lee, J. H. Bae, M. J. Kim, H. S. Lee, M. K. Lee, B. S. Chung, D. W. Kim, C. D. Kang, and S. H. Kim (2007)
J. Pharmacol. Exp. Ther. 322, 1084-1092
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The Multikinase Inhibitor Sorafenib Induces Apoptosis in Highly Imatinib Mesylate-Resistant Bcr/Abl+ Human Leukemia Cells in Association with Signal Transducer and Activator of Transcription 5 Inhibition and Myeloid Cell Leukemia-1 Down-Regulation.
M. Rahmani, T. K. Nguyen, P. Dent, and S. Grant (2007)
Mol. Pharmacol. 72, 788-795
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Development of an Integrated Assay for Detection of BCR-ABL RNA.
E. S. Winn-Deen, B. Helton, R. Van Atta, W. Wong, J. Peralta, J. Wang, G. J. Tsongalis, D. Belloni, D. Chan, J. R. Eshleman, et al. (2007)
Clin. Chem. 53, 1593-1600
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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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BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia.
C. A. Schiffer (2007)
N. Engl. J. Med. 357, 258-265
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Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer.
S. Rottenberg, A. O. H. Nygren, M. Pajic, F. W. B. van Leeuwen, I. van der Heijden, K. van de Wetering, X. Liu, K. E. de Visser, K. G. Gilhuijs, O. van Tellingen, et al. (2007)
PNAS 104, 12117-12122
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BCR-Tyrosine 177 Plays an Essential Role in Ras and Akt Activation and in Human Hematopoietic Progenitor Transformation in Chronic Myelogenous Leukemia.
S. Chu, L. Li, H. Singh, and R. Bhatia (2007)
Cancer Res. 67, 7045-7053
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Synergistic Interactions between Vorinostat and Sorafenib in Chronic Myelogenous Leukemia Cells Involve Mcl-1 and p21CIP1 Down-Regulation.
G. Dasmahapatra, N. Yerram, Y. Dai, P. Dent, and S. Grant (2007)
Clin. Cancer Res. 13, 4280-4290
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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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Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance.
M. Barok, J. Isola, Z. Palyi-Krekk, P. Nagy, I. Juhasz, G. Vereb, P. Kauraniemi, A. Kapanen, M. Tanner, G. Vereb, et al. (2007)
Mol. Cancer Ther. 6, 2065-2072
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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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Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells.
H. Konig, N. Hartel, B. Schultheis, M. Schatz, C. Lorentz, J. V. Melo, R. Hehlmann, A. Hochhaus, and P. La Rosee (2007)
Haematologica 92, 838-841
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c-Abl Tyrosine Kinase and Inhibition by the Cancer Drug Imatinib (Gleevec/STI-571).
B. Nagar (2007)
J. Nutr. 137, 1518S-1523S
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Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study.
A. Ray, S. W. Cowan-Jacob, P. W. Manley, J. Mestan, and J. D. Griffin (2007)
Blood 109, 5011-5015
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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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Chronic Myelogenous Leukemia Progenitors Display a Genetically Unstable Personality.
M. S. Rodrigues and M. Sattler (2007)
J Natl Cancer Inst 99, 662-663
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