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

Abstract

BACKGROUND:

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.

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.

• 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 Kleinschmidt, 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
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 49 Issue 18 Pg. 3936-44 (Dec 2013) ISSN: 1879-0852 [Electronic] England
• PMID: 24011934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• 2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
• Benzamides
• Phosphoinositide-3 Kinase Inhibitors
• Pyridones
• Pyrimidines
• mirdametinib
• Diphenylamine
• MAP2K2 protein, human
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• ras Proteins

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzamides (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Diphenylamine (administration & dosage, analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunoblotting
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Pyridones (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, genetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays
• ras Proteins (genetics, metabolism)