Submitted September 17, 2007
Accepted January 27, 2008
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 Gontarewicz, Stefan Balabanov, Gunhild Keller, Riccardo Colombo, Alessio Graziano, Enrico Pesenti, Daniel Benten, Carsten Bokemeyer, Walter Fiedler, Jurgen Moll, and Tim H. Brummendorf*
Klinik fur Onkologie und Hamatologie, Universitares Cancer Center (UCCH), Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
Nerviano Medical Sciences S.r.l.-Oncology, Milan, Italy
Klinik fur Gastroenterologie, Zentrum fur Innere Medizin, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
* Corresponding author; email: t.bruemmendorf{at}uke.uni-hamburg.de.
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 the novel small molecule inhibitor, PHA-739358 which selectively targets Bcr-Abl and Aurora kinases A-C. PHA-739358 exhibits strong antiproliferative and pro-apoptotic 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. Pharmacological synergism of IM and PHA-739358 was observed in leukemia cell lines with sub-total resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a down-stream 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 harbouring the T315I mutation.
Thus, PHA-739358 represents a promising new strategy for treatment of IM resistant BCR-ABL positive leukemias, including those harbouring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.
