4.3 Article

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

Journal

ONCOTARGET
Volume 7, Issue 37, Pages 59441-59457

Publisher

IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11118

Keywords

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

Funding

  1. Odense University Hospital, University of Southern Denmark
  2. Danish Counsel for Strategic Research, Strategic Research in Health, Food and Welfare
  3. Novo Nordisk Foundation
  4. Danish Cancer Society
  5. P. Carl Petersen Foundation
  6. Kathrine og Vigo Skovgaards Foundation
  7. Kornerup Foundation
  8. Swedish Cancer Society
  9. The Danish Cancer Society [R89-A6180] Funding Source: researchfish

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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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