title: TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells: a potential novel approach to the treatment of metastatic colorectal cancer.
abstract: It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5-fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP- 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy.
authors: Department of Oncology, Odense University Hospital, Odense, Denmark and University of Southern Denmark, Odense, Denmark.
authors: Line S
authors: LS
authors: Tarpgaard
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Maj Sofie
authors: MS
authors: Ørum-Madsen
authors: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark and Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Ib J
authors: IJ
authors: Christensen
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Cathrine
authors: C
authors: Nordgaard
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Julie
authors: J
authors: Noer
authors: Department of Oncology and K. G. Jebsen Centre for Colorectal Cancer Research, Oslo University Hospital, Oslo, Norway.
authors: Tormod K
authors: TK
authors: Guren
authors: Departments of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Bengt
authors: B
authors: Glimelius
authors: Department of Oncology, Haukeland University Hospital, Bergen, Norway.|Department of Clinical Science, University of Bergen, Bergen, Norway.
authors: Halfdan
authors: H
authors: Sorbye
authors: Department of Oncology, Oslo University Hospital, Oslo, Norway.
authors: Tone
authors: T
authors: Ikdahl
authors: Department of Genetics, Oslo University Hospital, Oslo, Norway.
authors: Elin H
authors: EH
authors: Kure
authors: Department of Oncology, Oslo University Hospital, Oslo, Norway.
authors: Kjell M
authors: KM
authors: Tveit
authors: Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark.
authors: Hans J
authors: HJ
authors: Nielsen
authors: Department of Oncology, Odense University Hospital, Odense, Denmark and University of Southern Denmark, Odense, Denmark.
authors: Per
authors: P
authors: Pfeiffer
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Nils
authors: N
authors: Brünner
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: José M A
authors: JM
authors: Moreira
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D000068818:Cetuximab / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood* / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077150:Oxaliplatin; D004815:Epidermal Growth Factor; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D005472:Fluorouracil
keywords: KRAS mutations; metastatic colorectal cancer; plasma TIMP-1; prediction; prognosis