title: HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma.
abstract: BACKGROUND
  Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs.
  
  
  METHODS
  Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors.
  
  
  RESULTS
  Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074.
  
  
  CONCLUSIONS
  Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients may potentially benefit from MET- or FGFR2-targeted therapies.
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: Y J
authors: YJ
authors: Liu
authors: Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200127, China.
authors: D
authors: D
authors: Shen
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: X
authors: X
authors: Yin
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: P
authors: P
authors: Gavine
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: T
authors: T
authors: Zhang
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: X
authors: X
authors: Su
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: P
authors: P
authors: Zhan
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: Y
authors: Y
authors: Xu
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: J
authors: J
authors: Lv
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: J
authors: J
authors: Qian
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: C
authors: C
authors: Liu
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: Y
authors: Y
authors: Sun
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: Z
authors: Z
authors: Qian
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: J
authors: J
authors: Zhang
authors: Department of Translational Science, Asia & Emerging Markets iMed, AstraZeneca R&D, 199 Liangjing Road, Shanghai 201203, China.
authors: Y
authors: Y
authors: Gu
authors: Department of General Surgery, Renji Hospital, School of Medicine, Shanghai Jiao-Tong University, Shanghai 200127, China.
authors: X
authors: X
authors: Ni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000077547:Crizotinib; D000077341:Lapatinib; D019859:Proto-Oncogene Proteins c-met; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; C115711:PD 173074; C508053:ERBB2 protein, human; C496353:FGFR2 protein, human; C491743:MET protein, human