The online version of this article (doi:10.1186/1476-4598-11-42) contains supplementary material, which is available to authorized users.
JM is employed by Nerviano Medical Sciences. The other authors declare no conflict of interest.
FF designed and performed research, collected, analyzed and interpreted data and wrote the manuscript. ML performed research and collected data; SS helped with design of experiments and performed research; JM interpreted data; JG interpreted data; NH designed experiments, analyzed and interpreted data and wrote the manuscript. All authors read and approved the final manuscript.
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemias (Ph-positive ALL) with clinically approved inhibitors of the Bcr/Abl tyrosine kinase frequently results in the emergence of a leukemic clone carrying the T315I mutation in Bcr/Abl, which confers resistance to these drugs. PHA-739358, an Aurora kinase inhibitor, was reported to inhibit the Bcr/Abl T315I mutant in CML cells but no preclinical studies have examined this in detail in human ALL.
We compared the sensitivity of human Bcr/Abl T315I, Bcr/Abl wild type and non-Bcr/Abl ALL cells to this drug. PHA-739358 inhibited proliferation and induced apoptosis independently of Bcr/Abl, the T315I mutation, or presence of the tumor suppressor p53, but the degree of effectiveness varied between different ALL samples. Since short-term treatment with a single dose of drug only transiently inhibited proliferation, we tested combination treatments of PHA-739358 with the farnesyltransferase inhibitor Lonafarnib, with vincristine and with dasatinib. All combinations reduced viability and cell numbers compared to treatment with a single drug. Clonogenic assays showed that 25 nM PHA-739358 significantly reduced the colony growth potential of Ph-positive ALL cells, and combined treatment with a second drug abrogated colony growth in this assay. PHA-739358 further effectively blocked Bcr/Abl tyrosine kinase activity and Aurora kinase B in vivo, and mice transplanted with human Bcr/Abl T315I ALL cells treated with a 3x 7-day cycle of PHA-739358 as mono-treatment had significantly longer survival.
PHA-739358 represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells.
Additional file 1: Figure S1. Dasatinib and vincristine potentiate the inhibitory effects of PHA-739358 on Ph-positive ALL cells. (A). Pt2 cells were treated with vincristine and PHA-739358 alone or together for 3 days. (B). UCSF02 cells were treated with dasatinib individually or combined with PHA-739358 for 3 days. Cell viability and viable cell numbers were assessed by Trypan blue exclusion assay. (*p< 0.05, **p<0.001). (TIFF 15 MB)12943_2012_1031_MOESM1_ESM.tiff
Additional file 2: Figure S2. PHA-739358 suppresses growth of Ph-positive ALL cells. Pt2 and UCSF02 cells were treated with PHA-739358 individually or combined with the FTI Lonafarnib, vincristine or dasatinib as indicated and analyzed in the colony formation assay. (*p< 0.05, **p <0.001). (TIFF 9 MB)12943_2012_1031_MOESM2_ESM.tiff
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- Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib)
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