Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab

Jacobs, Bart; Roock, Wendy De; Piessevaux, Hubert; Oirbeek, Robin Van; Biesmans, Bart; Schutter, Jef De; Fieuws, Steffen; Vandesompele, Jo; Peeters, Marc; Laethem, Jean‐Luc Van; Humblet, Yves; Penault‐Llorca, Frédérique; Hertogh, Gert De; Laurent‐Puig, Pierre; Cutsem, Éric Van; Tejpar, Sabine

doi:10.1200/jco.2008.21.3744

Cited by 314 publications

(248 citation statements)

References 15 publications

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“…Furthermore, screening of a 33 cell line panel across several indications demonstrated a strong correlation between sensitivity to cetuximab and MEDI3622. Cetuximab sensitivity is predicted by high EGFR ligand levels (31,32), strongly suggesting that high ligand levels predict MEDI3622 sensitivity as well. In support of this, MEDI3622 sensitive cell lines expressed high mRNA levels for at least one EGFR ligand, and no correlation was found between MEDI3622 sensitivity and mRNA levels of ADAM17, EGFR, HER2 or HER3 (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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ADAM17 is the primary sheddase for HER pathway ligands. We report the discovery of a potent and specific ADAM17 inhibitory antibody, MEDI3622, which induces tumor regression or stasis in many EGFR-dependent tumor models. The inhibitory activity of MEDI3622 correlated with EGFR activity both in a series of tumor models across several indications as well in as a focused set of head and neck patient-derived xenograft models. The antitumor activity of MEDI3622 was superior to that of EGFR/HER pathway inhibitors in the OE21 esophageal model and the COLO205 colorectal model suggesting additional activity outside of the EGFR pathway. Combination of MEDI3622 and cetuximab in the OE21 model was additive and eradicated tumors. Proteomics analysis revealed novel ADAM17 substrates that function outside of the HER pathways and may contribute toward the antitumor activity of the monoclonal antibody.

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Section: Discussionmentioning

confidence: 99%

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Rios-Doria¹,

Sabol²,

Chesebrough³

et al. 2015

Molecular Cancer Therapeutics

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“…16 Several studies have correlated the expression of these ligands with sensitivity to cetuximab monotherapy. The results showed a statistically longer progression free survival (PFS) among patients with high expression of epiregulin.…”

Section: Potential Positive Predictive Biomarkersmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

103

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s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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“…EREG is proteolytically cleaved by a disintegrin and a metalloprotease 17 (ADAM17) to release soluble ligand that binds to and activates ERBB1/EGFR and ERBB4/Her4 (2,10,11). Expression of EREG in adults is restricted (12)(13)(14), but EREG is overexpressed in a number of human breast and colorectal cancer cell lines and tumors (15)(16)(17)(18)(19). EREG also has been implicated as a "metastasis driver" in breast cancer cells selected to metastasize to the lung (20).…”

mentioning

confidence: 99%

Transformation of polarized epithelial cells by apical mistrafficking of epiregulin

Singh

Bogatcheva²,

Washington

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss of polarity and trafficking fidelity are thought to occur as a consequence of transformation; however, here we report that selective mistrafficking of the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from the basolateral to the apical cell surface drives transformation. Normally, EREG is preferentially delivered to the basolateral surface of polarized Madin-Darby canine kidney cells. EREG basolateral trafficking is regulated by a conserved tyrosine-based basolateral sorting motif in its cytoplasmic domain (YXXΦ: Y 156 ERV). Both Y156 and V159 are required for basolateral sorting of EREG, because Y156A and V159G substitutions redirect EREG to the apical cell surface. We also show that basolateral sorting of EREG is adaptor protein 1B-independent. Apical mistrafficking of EREG has a distinctive phenotype. In contrast to transient EGFR tyrosine phosphorylation after basolateral EREG stimulation, apical EREG leads to prolonged EGFR tyrosine phosphorylation, which may be related, at least in part, to a lack of negative regulatory Y1045 phosphorylation and subsequent ubiquitylation. Notably, Madin-Darby canine kidney cells stably expressing apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice compared with WT EREG-expressing cells.epithelial transformation | growth factor trafficking | receptor tyrosine kinase | protein sorting U nder normal physiological conditions, binding of endogenous ligand to EGF receptor (EGFR) is required for initiation of signal transduction. In polarized epithelial cells, EGFR is thought to be restricted to the basolateral surfaces (1). All seven EGFR ligands are produced as type 1 transmembrane proteins (2). Newly synthesized ligands are inserted into the plasma membrane, whereupon they undergo ectodomain cleavage to release soluble growth factor. We previously studied the biosynthesis and trafficking of EGF, TGF-α (TGFA), and amphiregulin (AREG) in polarized Madin-Darby canine kidney (MDCK) cells (3-5). These ligands have distinct motifs that govern their basolateral sorting (6-8). Of clinical relevance is a germline mutation in the basolateral sorting motif of EGF in individuals with isolated renal hypomagnesemia (9). In this autosomal recessive disorder, loss of EGF delivery to the basolateral surface impairs EGFR activity in the distal convoluted tubules, which is required for efficient magnesium absorption.Here we undertook the study of another EGFR ligand, epiregulin (EREG). EREG is proteolytically cleaved by a disintegrin and a metalloprotease 17 (ADAM17) to release soluble ligand that binds to and activates ERBB1/EGFR and ERBB4/Her4 (2, 10, 11). Expression of EREG in adults is restricted (12-14), but EREG is overexpressed in a number of human breast and colorectal cancer cell lines and tumors (15)(16)(17)(18)(19). EREG also has been implicated as a "metastasis dri...

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Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated With Cetuximab

Abstract: Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.

Cited by 314 publications

References 15 publications

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Transformation of polarized epithelial cells by apical mistrafficking of epiregulin

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