Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors

abstract

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Background

Ovarian cancer is the major cause of death from gynaecological malignancy with a 5 year survival of only ∼30% due to resistance to platinum and paclitaxel-based first line therapy. Dysregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and RAS/extracellular signal-regulated kinase (ERK) pathways is common in ovarian cancer, providing potential new targets for 2nd line therapy.

Methods

We determined the inhibition of proliferation of an extensive panel of ovarian cancer cell lines, encompassing all the major histotypes, by the dual PI3K/mTOR inhibitor PF-04691502 and a MEK inhibitor, PD-0325901. In addition, we analysed global gene expression, mutation status of key PI3K/mTOR and RAS/ERK pathway members and pathway activation to identify predictors of drug response.

Conclusions

These studies identify dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective new approach to treating ovarian cancer.