P2.15 Targeting Egfr and PI3K Pathways in Ovarian Cancer

Abstract

ABSTRACT The epidermal growth factor receptor is expressed in ovarian cancer, but agents targeting this pathway have shown little effect as single agents. We have examined the hypothesis that this is due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway using inhibitors of this pathway in combination with the EGFR inhibitors erlotinib and gefitinib in primary cell cultures and MCF10a isogenic cell lines (Horizon Discovery Ltd). PI3K mutation conferred increased activity of EGFR inhibitors against MCF10a cells in comparison with the parental cell line. Greatest sensitivity was seen within the PI3K mutated cells where IndexSUM values decreased from a relatively resistant index of 423 to a more sensitive level of 120 and 64 for the H1407R and E545K mutations of PI3KCA respectively. In ovarian tumours, the combination of ZSTK474 with EGFR inhibitors showed enhanced activity. This is encouraging, but phase I/II clinical trials with these agents should include pharmacodynamic endpoints and molecular characterisation to identify patients most likely to benefit from this strategy.