Centrosome aberrations and G1 phase arrest after in vitro and in vivo treatment with the SRC/ABL inhibitor dasatinib

Abstract

BackgroundDasatinib is a multitargeted inhibitor of ABL, the SRC family, and other tyrosine kinases. We sought to evaluate the effects of this drug on cell proliferation, centrosomes, mitotic spindles, and cell cycle progression in vitro and in vivo.

Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders

“…Tight regulation of tyrosine kinase activity has also been proven crucial for maintaining centrosomal integrity: both constitutive BCR-ABL activation and abrogation of tyrosine kinase activity by specific inhibitors have been shown to lead to centrosomal aberrations. 25,[41][42][43] We do not regard our conclusionFdrawn from a functional point of viewFas contradictory to previous studies. These have hypothesized a functional role of centrosomal tyrosine kinase activity based on the centrosomal localization of fusion proteins and have particularly relied on the detection of centrosomal signal transduction.…”

BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

“…They also confirmed the previous data that abnormal centrosome distribution, amplification and loss are more evident in the advanced stages of CML. Although the tyrosine kinase inhibitors are very potent, selective and successful therapeutic agents for treatment of leukemia as well as some solid tumors it can not be neglected that some reports indicated that they can lead to centrosome aberrations in cancer as well as normal cells Fabarius et al, 2008;Giehl et al, 2010). This was caused by blocking cells in the G1/S transition and the inhibition of cell growth which was followed by centrosomal aberrations.…”

Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure

“…In primary human cells dasatinib induced centrosome defects and delay of spindle formations. 13 The influence on the hematopoietic cells of CML patients was, therefore, of major interest.…”

“…Pre-treatment for the 71 patients consisted of imatinib, HU (n=48), IFN (n=49), cytosine arabinoside (AraC, n=11) and nilotinib (n=2) alone or in combination. Median duration of dasatinib therapy was nine months (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Dasatinib was stopped due to progressive disease in four, and because of hematologic toxicity in three patients.…”

“…[13][14][15] Data at onset of dasatinib treatment and at least one follow-up were available for each patient. Complete cytogenetic response (CCR) was defined as 0% major cytogenetic response (MCR) as 1-35%, minor cytogenetic response as 36-95%, and no response as 96-100% of Ph positive metaphases.…”