Research Papers:

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, Maj Sofie Ørum-Madsen, Ib J. Christensen, Cathrine Nordgaard, Julie Noer, Tormod K. Guren, Bengt Glimelius, Halfdan Sorbye, Tone Ikdahl, Elin H. Kure, Kjell M. Tveit, Hans J. Nielsen, Per Pfeiffer, Nils Brünner and José M. A. Moreira _

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Oncotarget. 2016; 7:59441-59457. https://doi.org/10.18632/oncotarget.11118

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Line S. Tarpgaard1,*, Maj Sofie Ørum-Madsen2,*, Ib J. Christensen3, Cathrine Nordgaard2, Julie Noer2, Tormod K. Guren4, Bengt Glimelius5, Halfdan Sorbye6,7, Tone Ikdahl8, Elin H. Kure9, Kjell M. Tveit8, Hans J. Nielsen10, Per Pfeiffer1,#, Nils Brünner2,#, José M. A. Moreira2,#

1Department of Oncology, Odense University Hospital, Odense, Denmark and University of Southern Denmark, Odense, Denmark

2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark and Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark

4Department of Oncology and K. G. Jebsen Centre for Colorectal Cancer Research, Oslo University Hospital Oslo, Norway

5Departments of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden

6Department of Oncology, Haukeland University Hospital, Bergen, Norway

7Department of Clinical Science, University of Bergen, Bergen, Norway

8Department of Oncology, Oslo University Hospital, Oslo, Norway

9Department of Genetics, Oslo University Hospital, Oslo, Norway

10Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark

*These authors contributed equally to this work

#These authors share senior authorship

Correspondence to:

José M. A. Moreira, email: [email protected]

Keywords: metastatic colorectal cancer, plasma TIMP-1, KRAS mutations, prognosis, prediction

Received: April 14, 2016     Accepted: June 17, 2016     Published: August 08, 2016


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.

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