|
|
Blood, 1 January 2006, Vol. 107, No. 1, pp. 293-300.
Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2005-06-2469.
 Previous Article | Next Article 
Submitted June 24, 2005
Accepted August 25, 2005
Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia (AML) by mutation of Asn-676 in the FLT3 tyrosine kinase domain
Florian Heidel, Fian K Solem, Frank Breitenbuecher, Daniel B Lipka, Stefan Kasper, H M Thiede, Christian Brandts, Hubert Serve, Johannes Roesel, Francis Giles, Eric Feldman, Gerhard Ehninger, Gary J Schiller, Stephen Nimer, Richard M Stone, Yanfeng Wang, Thomas Kindler, Pamela S Cohen, Christoph Huber, and Thomas Fischer*
3rd Medical Department, Johannes-Gutenberg University, Mainz, Germany
Thanares Analytik und Research GmbH, Dresden, Germany
Medical Department A, University of Muenster, Muenster, Germany
Novartis Pharma Inc., Basel, Switzerland
MD Anderson Cancer Center, Houston, TX, USA
Cornell University Cancer Center, New York, NY, USA
1st Medical Department, University Carl Gustav Carus, Dresden, Germany
UCLA Medical Center, Los Angeles, CA, USA
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Dana-Farber Cancer Institute, Boston, MA, USA
Novartis Oncology, Florham Park, NJ, USA
* Corresponding author; email: t.fischer{at}3-med.klinik.uni-mainz.de.
Activating mutations in the FLT3 receptor tyrosine kinase (TK) occur in approximately 35% of AML patients. Therefore, targeting mutated FLT3 by tyrosine kinase inhibitors (TKI) is an attractive therapeutic strategy. Currently, several FLT3 TKI are being tested in early clinical trials. As a proof of principle, these studies showed that inhibition of FLT3 TK activity may result in measurable clinical responses. Most of these responses are transient, however, in a subset of patients blast recurrence is preceded by an interval of prolonged remission. The etiology of clinical resistance to FLT3-TKI in AML is currently unclear but is of major significance for the development of future therapeutic strategies. We performed a search for potential mechanisms of resistance in a total of 6 AML patients relapsing upon various intervals of PKC412 treatment. In an index AML patient, an algorithm of various analyses was applied using clinical material: In vivo and in vitro investigation of primary blasts at the timepoint of relapse revealed persisting TK phosphorylation of FLT3 despite sufficient serum levels of PKC412. Through additional molecular analyses of clinical samples we identified a single amino acid substitution at position 676 (N676K) within the N-lobe of the FLT3 as the sole cause of clinical resistance to PKC412 in this patient. Screening of FLT3 sequence in additional 5 AML patients relapsing upon PKC412 treatment was negative for a mutation at amino acid position 676. Reconstitution experiments expressing the N676K mutant in 32D cells demonstrated that FLT3-ITD-N676K was sufficient to confer intermediate level of resistance to PKC412 in vitro. These studies point out that a genetically complex malignancy as AML may retain dependency on a single oncogenic signal.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. W. Lane, D. T. Scadden, and D. G. Gilliland
The leukemic stem cell niche: current concepts and therapeutic opportunities
Blood,
August 6, 2009;
114(6):
1150 - 1157.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Breitenbuecher, S. Schnittger, R. Grundler, B. Markova, B. Carius, A. Brecht, J. Duyster, T. Haferlach, C. Huber, and T. Fischer
Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor
Blood,
April 23, 2009;
113(17):
4074 - 4077.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Breitenbuecher, B. Markova, S. Kasper, B. Carius, T. Stauder, F. D. Bohmer, K. Masson, L. Ronnstrand, C. Huber, T. Kindler, et al.
A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML
Blood,
April 23, 2009;
113(17):
4063 - 4073.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Zhou, C. Bi, J. V. Janakakumara, S.-C. Liu, W.-J. Chng, K.-G. Tay, L.-F. Poon, Z. Xie, S. Palaniyandi, H. Yu, et al.
Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
Blood,
April 23, 2009;
113(17):
4052 - 4062.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. Peschel, and J. Duyster
FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro
Cancer Res.,
April 1, 2009;
69(7):
3032 - 3041.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. Jonsson
BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3
Blood,
March 5, 2009;
113(10):
2302 - 2311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Weisberg, J. Roesel, G. Bold, P. Furet, J. Jiang, J. Cools, R. D. Wright, E. Nelson, R. Barrett, A. Ray, et al.
Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells
Blood,
December 15, 2008;
112(13):
5161 - 5170.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-F. Huang, S.-K. Luo, J. Xu, J. Li, D.-R. Xu, L.-H. Wang, M. Yan, X.-R. Wang, X.-B. Wan, F.-M. Zheng, et al.
Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia
Blood,
March 1, 2008;
111(5):
2854 - 2865.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Haferlach
Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia
Hematology,
January 1, 2008;
2008(1):
400 - 411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. O'Hare, C. A. Eide, and M. W. N. Deininger
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia
Blood,
October 1, 2007;
110(7):
2242 - 2249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Raz, V. Nardi, M. Azam, J. Cortes, and G. Q. Daley
Farnesyl transferase inhibitor resistance probed by target mutagenesis
Blood,
September 15, 2007;
110(6):
2102 - 2109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Piloto, M. Wright, P. Brown, K.-T. Kim, M. Levis, and D. Small
Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways
Blood,
February 15, 2007;
109(4):
1643 - 1652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Mrozek, G. Marcucci, P. Paschka, S. P. Whitman, and C. D. Bloomfield
Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification?
Blood,
January 15, 2007;
109(2):
431 - 448.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Lierman, I. Lahortiga, H. Van Miegroet, N. Mentens, P. Marynen, and J. Cools
The ability of sorafenib to inhibit oncogenic PDGFR{beta} and FLT3 mutants and overcome resistance to other small molecule inhibitors
Haematologica,
January 1, 2007;
92(1):
27 - 34.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. A. Teicher
Protein kinase C as a therapeutic target.
Clin. Cancer Res.,
September 15, 2006;
12(18):
5336 - 5345.
[Full Text]
[PDF]
|
|
|
|
|
