The Activity of AT9283 in Acute Myeloid Leukemia in Vitro and in the Clinic Is Karyotype Dependent.

Abstract 4159

Aurora kinases (AK) A and B are overexpressed in a proportion of patients with acute myeloid leukemia (AML) and the level of overexpression correlates with their sensitivity to AK inhibition in vitro. We recently reported data from a dose escalation study of AT9238, a small molecule inhibitor of AKs in patients with refractory leukemias in which eight of 24 AML patients with relapsed/refractory AML achieved a ³ 33% reduction in bone marrow blasts and haematological improvement. All patients had received at least one line of previous therapy. Further analysis has revealed that of the eight patients with relapsed/refractory AML that benefited from treatment with AT9283 five had a normal karyotype and the remaining three patients showed evidence of isolated abnormalities of chromosome 7, including 7q loss.

Separately, we have reported that AT9283 inhibits the proliferation and survival of AML cell lines in vitro and suggested that those cell lines with complex karyotypic abnormalities responded differently from normal diploid lines.

In these experiments AML cell lines exhibit one of two phenotypes following exposure to AT9283; rapid induction of cell death at low nM concentrations (Phenotype 1) or endo-reduplication followed by cell death at a later time point (Phenotype 2). In both scenarios treatment with AT9283 results ultimately in cell death. Cell lines with a normal karyotype tended to undergo rapid apoptosis without evidence of endoreduplication at low concentrations of AT9283. These findings provide further support for the potential importance of karyotype as a determinant of outcome in the clinical study. This is the first indication that cytogenetics might be used to predict responsiveness to Aurora kinase inhibitors in the clinic.