AT9283, a Novel Pan-Aurora/JAK-2 Kinase Inhibitor Suppresses Tumor Growth In Aggressive B-Cell Non-Hodgkin's Lymphoma

Abstract 3930

Aurora kinases (A and B) are oncogenic serine/threonine kinases that play a central role in regulating the mitotic phase of the eukaryotic cell cycle. Auroras are over-expressed in numerous tumors including aggressive B-cell non-Hodgkin's lymphomas (B-NHL) and are considered validated oncology targets. AT9283 a pan-Aurora/JAK-2 inhibitor has undergone early phase trials in acute and chronic myeloid leukemia with promising anti-tumor activity. Hence, we hypothesized that 1) targeting mitosis with AT9283 would be effective in promoting apoptosis in aggressive B-NHL cell lines, and 2) addition of a microtubule targeting agent activating the spindle assembly checkpoint would lead to enhanced anti-tumor activity in a mouse xenograft model of mantle cell lymphoma (MCL).

AT9283 inhibited Aurora A and B activity as demonstrated by reducing phosphorylation of Aurora A and histone H3 as well as inhibition of cell proliferation (IC₅₀ of 0.02–1.6 μM) in a variety of aggressive B-NHL cell lines (diffuse large B-cell lymphoma, MCL and transformed follicular lymphoma). B-NHL cells treated with AT9283 exhibited endoreduplication confirming the mechanism of action of an Aurora kinase inhibitor. Treatment of B-NHL cells with AT9283 induced apoptosis demonstrated by flow cytometry and PARP-cleavage in a dose and time dependent manner. Aurora A over-expression has been demonstrated to override the spindle assembly checkpoint (SAC) and result in resistance to microtubule targeting agent (e.g. taxols and vinca alkaloids) induced apoptosis. At very low doses (5-50 nM) apoptosis was almost doubled in the combination (30%) compared to AT9283 or docetaxel alone (15%) compared to controls. A mouse xenograft MCL model (Granta-519) demonstrated that AT9283 (10 and 15 mg/kg) or docetaxel (10 mg/kg) alone had modest anti-tumor activity (10-20% tumor growth inhibition). However, AT9283 plus docetaxel demonstrated a statistically significant tumor growth inhibition of >60% over control. The body weights of all mice in all cohorts did not change significantly (within 10%) during the study and mice appeared to tolerate treatment(s) well. Together, our results suggest that AT9283 plus docetaxel may represent a novel therapeutic strategy in aggressive B-cell NHL and warrant early phase clinical trial evaluation [Funded by the Lymphoma SPORE, P50 CA130805501A1].