|
|
Blood, 15 April 2008, Vol. 111, No. 8, pp. 4355-4364.
Prepublished online as a Blood First Edition Paper on February 11, 2008; DOI 10.1182/blood-2007-09-113175.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I
Artur Gontarewicz1,
Stefan Balabanov1,
Gunhild Keller1,
Riccardo Colombo2,
Alessio Graziano2,
Enrico Pesenti2,
Daniel Benten3,
Carsten Bokemeyer1,
Walter Fiedler1,
Jürgen Moll2, and
Tim H. Brümmendorf1
1 Klinik für Onkologie und Hämatologie, Universitäres Cancer Center, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany;
2 Nerviano Medical Sciences Oncology, Milan, Italy; and
3 Klinik für Gastroenterologie, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL–positive and –negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34+ cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
R. B. Cohen, S. F. Jones, C. Aggarwal, M. von Mehren, J. Cheng, D. R. Spigel, F. A. Greco, M. Mariani, M. Rocchetti, R. Ceruti, et al.
A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-Hour Infusion with and without Granulocyte Colony-Stimulating Factor in a 14-Day Cycle in Patients with Advanced Solid Tumors
Clin. Cancer Res.,
November 1, 2009;
15(21):
6694 - 6701.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Steeghs, F. A.L.M. Eskens, H. Gelderblom, J. Verweij, J. W.R. Nortier, J. Ouwerkerk, C. van Noort, M. Mariani, R. Spinelli, P. Carpinelli, et al.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors
J. Clin. Oncol.,
October 20, 2009;
27(30):
5094 - 5101.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Boss, J. H. Beijnen, and J. H.M. Schellens
Clinical Experience with Aurora Kinase Inhibitors: A Review
Oncologist,
August 1, 2009;
14(8):
780 - 793.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Cortes
When Imatinib Fails, What Else Is There?
ASCO Educational Book,
January 1, 2009;
2009(1):
402 - 406.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L.-Y. Lu, J. L. Wood, L. Ye, K. Minter-Dykhouse, T. L. Saunders, X. Yu, and J. Chen
Aurora A Is Essential for Early Embryonic Development and Tumor Suppression
J. Biol. Chem.,
November 14, 2008;
283(46):
31785 - 31790.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. V. Melo and C. Chuah
Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond
Hematology,
January 1, 2008;
2008(1):
427 - 435.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
