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

// Line S. Tarpgaard 1, * , Maj Sofie Orum-Madsen 2, * , Ib J. Christensen 3 , Cathrine Nordgaard 2 , Julie Noer 2 , Tormod K. Guren 4 , Bengt Glimelius 5 , Halfdan Sorbye 6, 7 , Tone Ikdahl 8 , Elin H. Kure 9 , Kjell M. Tveit 8 , Hans J. Nielsen 10 , Per Pfeiffer 1, # , Nils Brunner 2, # , Jose M. A. Moreira 2, # 1 Department of Oncology, Odense University Hospital, Odense, Denmark and University of Southern Denmark, Odense, Denmark 2 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 3 The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark and Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark 4 Department of Oncology and K. G. Jebsen Centre for Colorectal Cancer Research, Oslo University Hospital Oslo, Norway 5 Departments of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden 6 Department of Oncology, Haukeland University Hospital, Bergen, Norway 7 Department of Clinical Science, University of Bergen, Bergen, Norway 8 Department of Oncology, Oslo University Hospital, Oslo, Norway 9 Department of Genetics, Oslo University Hospital, Oslo, Norway 10 Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark * These authors contributed equally to this work # These authors share senior authorship Correspondence to: Jose M. A. Moreira, email: jomo@sund.ku.dk Keywords: metastatic colorectal cancer, plasma TIMP-1, KRAS mutations, prognosis, prediction Received: April 14, 2016 Accepted: June 17, 2016 Published: August 08, 2016 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.