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

Abstract

// Susan Heavey 1 , Sinead Cuffe 1 , Stephen Finn 1 , Vincent Young 2 , Ronan Ryan 2 , Siobhan Nicholson 3 , Niamh Leonard 3 , Niall McVeigh 1 , Martin Barr 1 , Kenneth O’Byrne 4 , Kathy Gately 1 1 Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland 2 Department of Cardiothoracic Surgery, St. James’s Hospital, Dublin, Ireland 3 Department of Histopathology, St James Hospital, Dublin, Ireland 4 Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia Correspondence to: Susan Heavey, email: heaveys@tcd.ie Keywords: PI3K, MEK, NSCLC, lung, co-target Received: September 29, 2015     Accepted: September 12, 2016     Published: October 19, 2016 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.