Synergistic combinations of a novel PI3 Kinase inhibitor with Erlotinib and Rapamycin and the associated effects on downstream signalling

B256 It is now common practice to treat cancer patients with a combination of agents to increase upon the therapeutic benefit achievable by a single agent. It is therefore essential to investigate the activity of new agents in combination with existing therapies prior to embarking upon clinical trials.
 The phosphatidylinositol 3 kinase (PI3K) signalling pathway impacts upon many cellular processes, including cell proliferation, growth and survival. Deregulation of PI3K signalling is common in many types of cancers and hence this pathway has become an attractive target for the development of small molecule inhibitors. Here we investigate in vitro whether combining a PI3K inhibitor with existing therapies might provide additional anti-proliferative effects in tumour cell lines.
 In PC3 and SKOV-3 cells we show that PI3K inhibition leads to a synergistic inhibitory effect on proliferation when combined with either the Epidermal Growth Factor Receptor (EGFR) inhibitor Erlotinib, or the mammalian Target Of Rapamycin (mTOR) inhibitor, Rapamycin.
 By Western blotting it can be seen that the combination of PI3K and EGFR inhibition results in the blockade of both the PI3K and the MEK pathways and this may be contributing to the synergistic inhibition of cell proliferation observed with these two compounds. In addition, while it is apparent that Rapamycin alone increases the level of phosphorylated AKT (ser473) in PC3 cells, presumably through a feedback mechanism, this effect is blocked by combining with the PI3K inhibitor. Again this may suggest a mode of action by which these two compounds synergistically act to reduce the level of cell proliferation.
 In conclusion, the findings indicate that significant benefit can be achieved by combining targeted agents with complementary modes of action.