Format

Send to

Choose Destination
Oncotarget. 2016 Sep 13;7(37):59441-59457. doi: 10.18632/oncotarget.11118.

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.

Author information

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.

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.

KEYWORDS:

KRAS mutations; metastatic colorectal cancer; plasma TIMP-1; prediction; prognosis

PMID:
27509063
PMCID:
PMC5312323
DOI:
10.18632/oncotarget.11118
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center