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

Research output: Contribution to journalJournal articleResearchpeer-review

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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. / Tarpgaard, Line S; Ørum-Madsen, Maj Sofie; Christensen, Ib J; Nordgaard, Cathrine; Noer, Julie; Guren, Tormod K; Glimelius, Bengt; Sorbye, Halfdan; Ikdahl, Tone; Kure, Elin H; Tveit, Kjell M; phw435, phw435; Pfeiffer, Per; Brünner, Nils; Moreira, José.

In: OncoTarget, Vol. 7, No. 37, 08.08.2016, p. 59441-59457.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Tarpgaard, LS, Ørum-Madsen, MS, Christensen, IJ, Nordgaard, C, Noer, J, Guren, TK, Glimelius, B, Sorbye, H, Ikdahl, T, Kure, EH, Tveit, KM, phw435, P, Pfeiffer, P, Brünner, N & Moreira, J 2016, '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' OncoTarget, vol. 7, no. 37, pp. 59441-59457. https://doi.org/10.18632/oncotarget.11118

APA

Tarpgaard, L. S., Ørum-Madsen, M. S., Christensen, I. J., Nordgaard, C., Noer, J., Guren, T. K., ... Moreira, J. (2016). 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. OncoTarget, 7(37), 59441-59457. https://doi.org/10.18632/oncotarget.11118

Vancouver

Tarpgaard LS, Ørum-Madsen MS, Christensen IJ, Nordgaard C, Noer J, Guren TK et al. 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. OncoTarget. 2016 Aug 8;7(37):59441-59457. https://doi.org/10.18632/oncotarget.11118

Author

Tarpgaard, Line S ; Ørum-Madsen, Maj Sofie ; Christensen, Ib J ; Nordgaard, Cathrine ; Noer, Julie ; Guren, Tormod K ; Glimelius, Bengt ; Sorbye, Halfdan ; Ikdahl, Tone ; Kure, Elin H ; Tveit, Kjell M ; phw435, phw435 ; Pfeiffer, Per ; Brünner, Nils ; Moreira, José. / 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. In: OncoTarget. 2016 ; Vol. 7, No. 37. pp. 59441-59457.

Bibtex

@article{4671ee2e44804cd9a614dce78829727e,
title = "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",
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.",
author = "Tarpgaard, {Line S} and {\O}rum-Madsen, {Maj Sofie} and Christensen, {Ib J} and Cathrine Nordgaard and Julie Noer and Guren, {Tormod K} and Bengt Glimelius and Halfdan Sorbye and Tone Ikdahl and Kure, {Elin H} and Tveit, {Kjell M} and phw435 phw435 and Per Pfeiffer and Nils Br{\"u}nner and Jos{\'e} Moreira",
year = "2016",
month = "8",
day = "8",
doi = "10.18632/oncotarget.11118",
language = "English",
volume = "7",
pages = "59441--59457",
journal = "OncoTarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "37",

}

RIS

TY - JOUR

T1 - TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells

T2 - A potential novel approach to the treatment of metastatic colorectal cancer

AU - Tarpgaard, Line S

AU - Ørum-Madsen, Maj Sofie

AU - Christensen, Ib J

AU - Nordgaard, Cathrine

AU - Noer, Julie

AU - Guren, Tormod K

AU - Glimelius, Bengt

AU - Sorbye, Halfdan

AU - Ikdahl, Tone

AU - Kure, Elin H

AU - Tveit, Kjell M

AU - phw435, phw435

AU - Pfeiffer, Per

AU - Brünner, Nils

AU - Moreira, José

PY - 2016/8/8

Y1 - 2016/8/8

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.11118

DO - 10.18632/oncotarget.11118

M3 - Journal article

VL - 7

SP - 59441

EP - 59457

JO - OncoTarget

JF - OncoTarget

SN - 1949-2553

IS - 37

ER -

ID: 165143377