The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer

Francisco J. Sánchez-Martín, Beatriz Bellosillo, Mariona Gelabert-Baldrich, Alba Dalmases, Israel Cañadas, Joana Vidal, Alejandro Martinez, Guillem Argilés, Giulia Siravegna, Sabrina Arena, Klaus Koefoed, Laura Visa, Oriol Arpí, Ivan David Horak, Mar Iglesias, Christopher Stroh, Michael Kragh, Ana Rovira, Joan Albanell, Josep Tabernero & 2 others Alberto Bardelli, Clara Montagut

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials.

Original languageEnglish
Pages (from-to)3260-3267
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number13
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

Anti-Idiotypic Antibodies
Colorectal Neoplasms
Mutation
Heterografts
Cetuximab
Ligands
Drug Receptors
Neoplasms
Tumor Cell Line
Pharmaceutical Preparations
Disease Progression
Cell Survival
Research Design
Biomarkers
Phosphorylation
Clinical Trials
panitumumab
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sánchez-Martín, F. J., Bellosillo, B., Gelabert-Baldrich, M., Dalmases, A., Cañadas, I., Vidal, J., ... Montagut, C. (2016). The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer. Clinical Cancer Research, 22(13), 3260-3267. https://doi.org/10.1158/1078-0432.CCR-15-2400

The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer. / Sánchez-Martín, Francisco J.; Bellosillo, Beatriz; Gelabert-Baldrich, Mariona; Dalmases, Alba; Cañadas, Israel; Vidal, Joana; Martinez, Alejandro; Argilés, Guillem; Siravegna, Giulia; Arena, Sabrina; Koefoed, Klaus; Visa, Laura; Arpí, Oriol; Horak, Ivan David; Iglesias, Mar; Stroh, Christopher; Kragh, Michael; Rovira, Ana; Albanell, Joan; Tabernero, Josep; Bardelli, Alberto; Montagut, Clara.

In: Clinical Cancer Research, Vol. 22, No. 13, 01.07.2016, p. 3260-3267.

Research output: Contribution to journalArticle

Sánchez-Martín, FJ, Bellosillo, B, Gelabert-Baldrich, M, Dalmases, A, Cañadas, I, Vidal, J, Martinez, A, Argilés, G, Siravegna, G, Arena, S, Koefoed, K, Visa, L, Arpí, O, Horak, ID, Iglesias, M, Stroh, C, Kragh, M, Rovira, A, Albanell, J, Tabernero, J, Bardelli, A & Montagut, C 2016, 'The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer', Clinical Cancer Research, vol. 22, no. 13, pp. 3260-3267. https://doi.org/10.1158/1078-0432.CCR-15-2400
Sánchez-Martín, Francisco J. ; Bellosillo, Beatriz ; Gelabert-Baldrich, Mariona ; Dalmases, Alba ; Cañadas, Israel ; Vidal, Joana ; Martinez, Alejandro ; Argilés, Guillem ; Siravegna, Giulia ; Arena, Sabrina ; Koefoed, Klaus ; Visa, Laura ; Arpí, Oriol ; Horak, Ivan David ; Iglesias, Mar ; Stroh, Christopher ; Kragh, Michael ; Rovira, Ana ; Albanell, Joan ; Tabernero, Josep ; Bardelli, Alberto ; Montagut, Clara. / The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 13. pp. 3260-3267.
@article{b81902fe1d314b7b9eac3f2c2b174e83,
title = "The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer",
abstract = "Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials.",
author = "S{\'a}nchez-Mart{\'i}n, {Francisco J.} and Beatriz Bellosillo and Mariona Gelabert-Baldrich and Alba Dalmases and Israel Ca{\~n}adas and Joana Vidal and Alejandro Martinez and Guillem Argil{\'e}s and Giulia Siravegna and Sabrina Arena and Klaus Koefoed and Laura Visa and Oriol Arp{\'i} and Horak, {Ivan David} and Mar Iglesias and Christopher Stroh and Michael Kragh and Ana Rovira and Joan Albanell and Josep Tabernero and Alberto Bardelli and Clara Montagut",
year = "2016",
month = "7",
day = "1",
doi = "10.1158/1078-0432.CCR-15-2400",
language = "English",
volume = "22",
pages = "3260--3267",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "13",

}

TY - JOUR

T1 - The first-in-class anti-EGFR antibody mixture Sym004 overcomes cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer

AU - Sánchez-Martín, Francisco J.

AU - Bellosillo, Beatriz

AU - Gelabert-Baldrich, Mariona

AU - Dalmases, Alba

AU - Cañadas, Israel

AU - Vidal, Joana

AU - Martinez, Alejandro

AU - Argilés, Guillem

AU - Siravegna, Giulia

AU - Arena, Sabrina

AU - Koefoed, Klaus

AU - Visa, Laura

AU - Arpí, Oriol

AU - Horak, Ivan David

AU - Iglesias, Mar

AU - Stroh, Christopher

AU - Kragh, Michael

AU - Rovira, Ana

AU - Albanell, Joan

AU - Tabernero, Josep

AU - Bardelli, Alberto

AU - Montagut, Clara

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials.

AB - Purpose: Approved anti-EGFR antibodies cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two nonoverlapping anti-EGFR mAbs that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab, and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored EGFR mutation in the post-cetuximab tumor sample. Results: Contrary to cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof-of-principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials.

UR - http://www.scopus.com/inward/record.url?scp=84964634075&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964634075&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-2400

DO - 10.1158/1078-0432.CCR-15-2400

M3 - Article

VL - 22

SP - 3260

EP - 3267

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 13

ER -