Type

Journal Article

Authors

Kathy Gately
Kenneth O'Byrne
Martin Barr
Niall McVeigh
Niamh Leonard
Siobhan Nicholson
Ronan Ryan
Vincent Young
Stephen Finn
Sinead Cuffe
and 1 others

Subjects

Medicine & Nursing

Topics
anti apoptotic mortality rates intervention strategies synergy cell lines non small cell lung cancer nsclc clinical trials inhibition

In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC. (2015)

Abstract Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach.Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines.PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti-proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines.This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently.
Collections Ireland -> Trinity College Dublin -> PubMed

Full list of authors on original publication

Kathy Gately, Kenneth O'Byrne, Martin Barr, Niall McVeigh, Niamh Leonard, Siobhan Nicholson, Ronan Ryan, Vincent Young, Stephen Finn, Sinead Cuffe and 1 others

Experts in our system

1
Kathy Gately
Trinity College Dublin
Total Publications: 22
 
2
Kenneth J O'Byrne
Trinity College Dublin
Total Publications: 37
 
3
Martin P Barr
Trinity College Dublin
Total Publications: 27
 
4
Niamh Leonard
Trinity College Dublin
Total Publications: 6
 
5
Siobhan Nicholson
Trinity College Dublin
Total Publications: 3
 
6
Ronan Ryan
Trinity College Dublin
Total Publications: 3
 
7
Stephen P Finn
Trinity College Dublin
Total Publications: 60
 
8
Sinead Cuffe
Trinity College Dublin
Total Publications: 21