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

• DOI: 10.1016/j.ejca.2013.08.007
• Publication Date: 2013-09-03T17:45:23Z
• Authors: Karen E. Sheppard; Carleen Cullinane; Katherine M. Hannan; Meaghan Wall; Joanna Chan; Frances Barber; Jung Foo; Donald Cameron; Amelia Neilsen; Pui Ng; Jason Ellul; Margarete Kleinsc...; Kathryn M. Kinross; David D. Bowtell; James G. Christensen; Rodney J. Hicks; Ricky W. Johnstone; Grant A. McArthur; Ross D. Hannan; Wayne A. Phillips; Richard B. Pearson
• Keywords: Kinase; Immunoblotting; MAP Kinase Kinase 2; MAP Kinase Kinase 1; 610; Mice, Nude; Therapeutics; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Ovarian cancer; Cell Line, Tumor; 616; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; 1306 Cancer Research; Extracellular Signal-Regulated MAP Kinases; Cell Proliferation; Ovarian Neoplasms; Mice, Inbred BALB C; 0303 health sciences; Gene Expression Profiling; Diphenylamine; Drug Synergism; 3. Good health; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Benzamides; 2730 Oncology; Female

Ovarian cancer is the major cause of death from gynaecological malignancy with a 5year 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.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.PF-04691502 inhibits proliferation of the majority of cell lines with potencies that correlate with the extent of pathway inhibition. Resistant cell lines were characterised by activation of the RAS/ERK pathway as indicated by differential gene expression profiles and pathway activity analysis. PD-0325901 suppressed growth of a subset of cell lines that were characterised by high basal RAS/ERK signalling. Strikingly, using PF-04691502 and PD-0325901 in combination resulted in synergistic growth inhibition in 5/6 of PF-04691502 resistant cell lines and two cell lines resistant to both single agents showed robust synergistic growth arrest. Xenograft studies confirm the utility of combination therapy to synergistically inhibit tumour growth of PF-04691502-resistant tumours in vivo.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.