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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
Odense Univ Hosp, Dept Oncol, Odense, Denmark.;Univ Southern Denmark, Odense, Denmark..
Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
Rigshosp, Finsen Lab, Copenhagen, Denmark.;Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark..
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 37, 59441-59457 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 7, no 37, 59441-59457 p.
Keyword [en]
metastatic colorectal cancer, plasma TIMP-1, KRAS mutations, prognosis, prediction
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-310032DOI: 10.18632/oncotarget.11118ISI: 000387153900054PubMedID: 27509063OAI: oai:DiVA.org:uu-310032DiVA: diva2:1055197
Funder
Novo NordiskSwedish Cancer Society
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2016-12-12Bibliographically approved

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