154P - Co-targeting the PI3K-mTOP & MEK pathways in NSCLC

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Basic Science
Lung and other Thoracic Tumours
Presenter Susan Heavey
Authors S. Heavey1, M. Barr2, A. Ahmad3, A. Davies3, K.J. O'Byrne2, K.A. Gately2
  • 1Trinity College Dublin, Dublin/IE
  • 2Clinical Medicine, Trinity College Dublin, Dublin/IE
  • 3Clinical Medicine, Trinity College Dublin, D8 - Dublin 8/IE

Abstract

The PI3K/Akt/mTOR and MAP/ERK kinase (MEK) pathways regulate cell growth and proliferation and are often dysregulated in cancer due to mutation, amplification, deletion, methylation and post-translational modifications. We and others have shown that activation of the PI3K pathway in Non Small Cell Lung Cancer (NSCLC) leads to a more aggressive, drug-resistant disease which correlates to poor prognosis for patients. Combinations of PI3K and MEK and inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signalling pathways. The selection of appropriate patient cohorts who will benefit from this targeted therapy, using biomarkers, is key to the success of these inhibitors. GDC-0941 is a PI3K targeted inhibitor which is currently in phase II trials for combination treatment with carboplatin, paclitaxel and bevacizumab in patients with previously untreated advanced or recurrent NSCLC. GDC-0980 is a selective dual inhibitor of PI3K and mTOR, which is currently in phase I trials for combination treatment with bevacizumab, trastuzumab and capecitabine in solid tumours. GDC-0973 is a MEK targeted inhibitor which is currently in Phase I clinical trials for treatment of patients with solid tumours in combination with GDC-0941. The aim of this study is to investigate the effects of GDC-0941, GDC-0980 and GDC-0973 alone and in combination on a panel of NSCLC cell lines and to develop cell line models resistant to dual inhibitor GDC-0980 which will then be characterised to elucidate mechanisms involved in acquired resistance. The effects of GDC-0941 and GDC-0980 on pAkt, pS6 and cPARP levels, and the effects of GDC-0973 on MAPK and Bim levels were analysed by Western blot. The effects of these inhibitors alone and in combination on cell proliferation and apoptosis were analysed by BrdU assay and by multiparameter apoptosis assays (using High Content Analysis) respectively. The results varied across the panel of cell lines, however the dual inhibitor GDC-0980 demonstrated more significant anti-proliferative and pro-apoptotic effects than PI3K inhibitor GDC-0941. IC50 values for GDC-0980 are currently being used to treat the panel of cell lines in order to develop cell line models of resistance.

Disclosure

All authors have declared no conflicts of interest.