title: In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC.
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.
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Susan
authors.initials: S
authors.lastname: Heavey
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Sinead
authors.initials: S
authors.lastname: Cuffe
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.affiliation: Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Young
authors.affiliation: Department of Cardiothoracic Surgery, St. James's Hospital, Dublin, Ireland.
authors.forename: Ronan
authors.initials: R
authors.lastname: Ryan
authors.affiliation: Department of Histopathology, St James Hospital, Dublin, Ireland.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Nicholson
authors.affiliation: Department of Histopathology, St James Hospital, Dublin, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: Leonard
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Niall
authors.initials: N
authors.lastname: McVeigh
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Barr
authors.affiliation: Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology, Brisbane, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Kathy
authors.initials: K
authors.lastname: Gately
mesh_terms: D000072283:A549 Cells; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D001384:Azetidines; D007191:Indazoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C574276:cobimetinib
keywords: MEK; NSCLC; PI3K; co-target; lung