The Aurora family of
kinases, play a fundamental role in cell division and are overexpressed in several
cancers including colon. The activity of
barasertib-hQPA, a selective inhibitor of
Aurora-B kinase (ABK) was investigated in a range of preclinical models of
gastrointestinal cancer. Treatment with
barasertib-hQPA produced anti-proliferative and cytotoxic effects across a panel of human
colorectal cancer (CRC) cell lines in vitro.
Prodrug,
barasertib [48-h subcutaneous (s.c.) infusion; 150 mg/kg/day] inhibited the growth of SW620, Colo205, HCT116 human
colorectal tumor xenografts in nude mice significantly (Student's t-test, P<0.05, n=10-12 per group). Flow cytometric analysis of single cells from disaggregated
barasertib-treated SW620
tumors revealed a decrease in phosphorylated
histone H3 (phH3) and an increase in
tumor cells with ≥4N
DNA content P<0.05). The activity of
barasertib was then examined in ApcMin/+ mice, a spontaneous model of early intestinal
neoplasia. Macroscopic evaluation of the small intestine revealed that
barasertib treatment [25 mg/kg intra-peritoneal (i.p.) Q1Dx4 each week for 3 weeks] of 8-week old ApcMin/+ mice produced a 39% reduction in macroadenoma number (P=0.02) and a 43% reduction in overall
adenoma burden (P=0.02) compared with vehicle-treated controls. Quantification of microscopic
adenomas revealed a >64% reduction in the number of
adenomas spanning more than one villus. Histological analysis of these
adenomas revealed a number of distinct changes in
barasertib-treated ApcMin/+ mice, including a 94% reduction in the proportion of phospho-
histone H3-positive cells (P<0.001) and a 53% reduction in the number of cells per
adenoma (P=0.001). These results provide a scientific rationale for investigating ABK inhibitors as a treatment for
intestinal cancer.