Abstract

Future cancer treatment regimes may involve novel drug combinations aimed at targeting different pathways involved in tumour proliferation and survival. Understanding the mechanisms involved in such combinations and identifying the optimum schedule/sequence, will be key to guiding clinical development.

The Aurora kinases play a critical role in mitosis and have been suggested as promising targets for therapy due to their frequent over expression in a variety of tumours. AZD1152 is a selective Aurora B kinase inhibitor, with a novel anti-tumour mechanism of action, inducing endoreduplication, apoptosis and inhibition of cytokinesis. The MAPK signalling pathway is implicated in uncontrolled cell proliferation and cell survival in many cancers. AZD6244 (ARRY-142886), a selective, ATP non-competitive inhibitor of MEK1/2, has demonstrated G1 arrest and anti-tumour activity in a range of preclinical models.

In the present study, we dosed AZD1152 and AZD6244 in combination to nude mice bearing human NSCLC tumour (Calu-6) xenografts. Pharmacodynamic analysis of Calu-6 xenografts treated with either AZD1152 or AZD6244 as monotherapies (MonTx) indicated downstream biomarker effects in accordance with their targets (for e.g. suppression of phosphorylation of histone H3 and ERK, respectively). When the same doses of AZD1152 (150mg/Kg/day s.c. for 2 days via osmotic minipumps) or AZD6244 (25mg/kg/BID p.o.) were dosed in a chronic disease setting, both drugs significantly suppressed Calu-6 tumour growth (versus respective vehicle groups, p<0.005). In combination, the two drugs were dosed in sequence, either AZD1152 AZD6244 or AZD6244 AZD1152. Whilst both sequences proved superior to the vehicle arms, only the AZD1152 AZD6244 proved superior to both MonTx arms in terms of apoptosis induction and tumour growth inhibition.

These data indicate a promising therapeutic strategy for combining AZD1152 and AZD6244, and suggest that the sequence of drug administration maybe critical when combining these inhibitors. Both AZD1152 and AZD6244 are currently in clinical trials.