Abstract 453: MEK activation is associated with a molecular subgroup in high grade serous ovarian cancer
Authors: McCabe Nuala , Gourley Charlie , McGavigan Andrena , Michie Caroline O. , McGivern Niamh , Churchman Michael , O’Brien Eamonn J. , Hill Laura , Davison Timothy S. , Williams Alistair , McCluggage Glenn , Keating Karen E. , Harkin Denis P. , Kennedy Richard D. 
Published: July 2016

Abstract
Introduction
We have previously defined 3 molecular subgroups of High grade serous ovarian cancer (HGSOC), ‘Angio’, ‘Immune’ and ‘Angio_immune’ subgroups using gene expression data from 265 FFPE HGSOC samples obtained from treatment naive patients and who were subsequently treated with platinum-based standard of care (SoC) chemotherapy (carboplatin +/- paclitaxel) (Gourley, et al. J Clin Oncol 32:5s, 2014). Patients within these 3 molecular subgroups respond differently to SOC treatment. The immune subgroup has the best outcome compared to the Angio and Angio_immune subgroups (HR of 0.63 and 0.66 respectively on multivariate analysis). Since it has previously been shown that the MAPK pathway is an important mediator of cisplatin resistance in ovarian cancer, we wanted to investigate if the MAPK pathway was associated with one of the poor prognosis subgroups.
Methods
A gene signature that could detect each of the subgroups Angio, Immune and Angio_immune was generated from the clinical samples. Data from the Cancer Genome Atlas (TCGA) Project was used to test for correlation between each subgroup and phospho-MEK as measured by Reverse Phase Proteomic Array (RPPA). Sensitivity to the MEK inhibitor trametinib (GSK1120212) and cisplatin was determined by 10-day colony formation assay.
Results
We found a statistically significant association between the Angio_immune subgroup signature and Phospho-MEK (serine 217/221) expression (p = 0.047) indicating activation of the MAPK pathway in this subgroup. Additionally we have demonstrated that the Angio_immune subgroup signature is suppressed by MEK inhibition (p = 0.0055) and elevated by KRAS, NRAS and MEK1 overexpression in cell line models (0.0072, 0.0004 and &lt;0.0001). These effects were specific to the Angio_immune subgroup signature as there was no association with the Angio or immune subgroup signatures. Additionally the Angio_immune gene signature could predict resistance to cisplatin and sensitivity to MEK inhibitors in a panel of breast and ovarian cancer cell line models (p = 0.0017 and p = 0.0091). Acquired resistance to cisplatin in cell line models was also associated with MEK activation and an elevated Angio_immune gene signature score, which could be reversed by a MEK inhibitor.
Conclusion
We have identified a molecular subgroup in HGSOC that is associated with MAPK signalling. A gene signature to detect this subgroup from formalin fixed paraffin embedded samples has been developed and predicts sensitivity to MEK inhibitors in pre-clinical model systems. Further work aims to validate the signature in clinical samples from patients treated with a MEK inhibitor.
Citation Format: Nuala McCabe, Charlie Gourley, Andrena McGavigan, Caroline O. Michie, Niamh McGivern, Michael Churchman, Eamonn J. O’Brien, Laura Hill, Timothy S. Davison, Alistair Williams, Glenn McCluggage, Karen E. Keating, Denis P. Harkin, Richard D. Kennedy. MEK activation is associated with a molecular subgroup in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 453.