title: Importance of the type I insulin-like growth factor receptor in HER2, FGFR2 and MET-unamplified gastric cancer with and without Ras pathway activation.
abstract: Amplification of seven oncogenes: HER2, EGFR, FGFR1, FGFR2, MET, KRAS and IGF1R has been identified in gastric cancer. The first five are targeted therapeutically in patients with HER2-positivity, FGFR2- or MET-amplification but the majority of patients are triple-negative and require alternative strategies. Our aim was to evaluate the importance of the IGF1R tyrosine kinase in triple-negative gastric cancer with and without oncogenic KRAS, BRAF or PI3K3CA mutations. Cell lines and metastatic tumor cells isolated from patients expressed IGF1R, and insulin-like growth factor-1 (IGF-1) activated the PI3-kinase/Akt and Ras/Raf/MAP-kinase pathways. IGF-1 protected triple-negative cells from caspase-dependent apoptosis and anoikis. Protection was mediated via the PI3-kinase/Akt pathway. Remarkably, IGF-1-dependent cell survival was greater in patient samples. IGF-1 stimulated triple-negative gastric cancer cell growth was prevented by IGF1R knockdown and Ras/Raf/MAP-kinase pathway inhibition. The importance of the receptor in cell line and metastatic tumor cell growth in serum-containing medium was demonstrated by knockdown and pharmacological inhibition with figitumumab. The proportions of cells in S-phase and mitotic-phase, and Ras/Raf/MAP-kinase pathway activity, were reduced concomitantly. KRAS-addicted and BRAF-impaired gastric cancer cells were particularly susceptible. In conclusion, IGF1R and the IGF signal transduction pathway merit consideration as potential therapeutic targets in patients with triple-negative gastric cancer.
authors.affiliation: Northern Institute for Cancer Research, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Saisana
authors.affiliation: Northern Institute for Cancer Research, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.|Northern Oesophago-Gastric Cancer Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
authors.forename: S Michael
authors.initials: SM
authors.lastname: Griffin
authors.affiliation: Northern Institute for Cancer Research, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.|Newcastle University Institute for Ageing, Department of Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
authors.forename: Felicity E B
authors.initials: FE
authors.lastname: May
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000737:chemistry / Q000473:pathology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D048493:Proto-Oncogene Proteins B-raf; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; D018631:ras Proteins; C000597236:IGF1R protein, human; C117307:KRAS protein, human; C508053:ERBB2 protein, human; C496353:FGFR2 protein, human; C491743:MET protein, human; C482119:BRAF protein, human
keywords: BRAF-impaired; KRAS-addicted; cell survival and proliferation; gastric cancer; type I IGF receptor