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

Sheppard, Karen E., Cullinane, Carleen, Hannan, Katherine M., Wall, Meaghan, Chan, Joanna, Barber, Frances, Foo, Jung, Cameron, Donald, Neilsen, Amelia, Ng, Pui, Ellul, Jason, Kleinschmidt, Margarete, Kinross, Kathryn M., Bowtell, David D., Christensen, James G., Hicks, Rodney J., Johnstone, Ricky W., McArthur, Grant A., Hannan, Ross D., Phillips, Wayne A. and Pearson, Richard B. (2013) Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. European Journal of Cancer, 49 18: 3936-3944. doi:10.1016/j.ejca.2013.08.007


Author Sheppard, Karen E.
Cullinane, Carleen
Hannan, Katherine M.
Wall, Meaghan
Chan, Joanna
Barber, Frances
Foo, Jung
Cameron, Donald
Neilsen, Amelia
Ng, Pui
Ellul, Jason
Kleinschmidt, Margarete
Kinross, Kathryn M.
Bowtell, David D.
Christensen, James G.
Hicks, Rodney J.
Johnstone, Ricky W.
McArthur, Grant A.
Hannan, Ross D.
Phillips, Wayne A.
Pearson, Richard B.
Title Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors
Journal name European Journal of Cancer   Check publisher's open access policy
ISSN 0959-8049
1879-0852
Publication date 2013
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ejca.2013.08.007
Open Access Status
Volume 49
Issue 18
Start page 3936
End page 3944
Total pages 9
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Collection year 2014
Language eng
Subject 1306 Cancer Research
2730 Oncology
Abstract 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. Results 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. 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.
Keyword Ovarian cancer
Kinase
Therapeutics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
 
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