title: Insights into significance of combined inhibition of MEK and m-TOR signalling output in KRAS mutant non-small-cell lung cancer.
abstract: We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines.
  
  
  
  In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively.
  
  
  
  GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10(-4)). There was no significant difference in GI caused by maximal m-TOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRAS(M) cell lines (79% vs 61%, P=0.017).
  
  
  
  m-TOR inhibition was more critical to GI than MEK inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRAS(M) cells.
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Département de Biologie et Pathologie Médicales, Villejuif, F-94805, France.|The Institute of Cancer Research, Clinical Pharmacology and Trials Team, London, SM2 5PT, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Broutin
authors.affiliation: The Institute of Cancer Research, Clinical Pharmacology and Trials Team, London, SM2 5PT, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Stewart
authors.affiliation: The Institute of Cancer Research, Clinical Pharmacology and Trials Team, London, SM2 5PT, UK.
authors.forename: Parames
authors.initials: P
authors.lastname: Thavasu
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Département de Biologie et Pathologie Médicales, Villejuif, F-94805, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Département de Biologie et Pathologie Médicales, Villejuif, F-94805, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bidart
authors.affiliation: The Institute of Cancer Research, Clinical Pharmacology and Trials Team, London, SM2 5PT, UK.
authors.forename: Udai
authors.initials: U
authors.lastname: Banerji
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases