The genomic landscape of response to EGFR blockade in colorectal cancer

Andrea Bertotti, Eniko Papp, Siân Jones, Vilmos Adleff, Valsamo Anagnostou, Barbara Lupo, Mark Sausen, Jillian Phallen, Carolyn A. Hruban, Collin Tokheim, Noushin Niknafs, Monica Nesselbush, Karli Lytle, Francesco Sassi, Francesca Cottino, Giorgia Migliardi, Eugenia R. Zanella, Dario Ribero, Nadia Russolillo, Alfredo Mellano & 15 others Andrea Muratore, Gianluca Paraluppi, Mauro Salizzoni, Silvia Marsoni, Michael Kragh, Johan Lantto, Andrea Cassingena, Qing Kay Li, Rachel Karchin, Robert Scharpf, Andrea Sartore-Bianchi, Salvatore Siena, Luis A. Diaz, Livio Trusolino, Victor E. Velculescu

Research output: Contribution to journalArticle

Abstract

Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

LanguageEnglish (US)
Pages263-267
Number of pages5
JournalNature
Volume526
Issue number7572
DOIs
StatePublished - Oct 8 2015

Fingerprint

Epidermal Growth Factor Receptor
Colorectal Neoplasms
Neoplasms
Therapeutics
Transplants
Antibodies
Genes
Exome
Gene Targeting
Receptor Protein-Tyrosine Kinases
Monoclonal Antibodies
Mutation

ASJC Scopus subject areas

  • General

Cite this

The genomic landscape of response to EGFR blockade in colorectal cancer. / Bertotti, Andrea; Papp, Eniko; Jones, Siân; Adleff, Vilmos; Anagnostou, Valsamo; Lupo, Barbara; Sausen, Mark; Phallen, Jillian; Hruban, Carolyn A.; Tokheim, Collin; Niknafs, Noushin; Nesselbush, Monica; Lytle, Karli; Sassi, Francesco; Cottino, Francesca; Migliardi, Giorgia; Zanella, Eugenia R.; Ribero, Dario; Russolillo, Nadia; Mellano, Alfredo; Muratore, Andrea; Paraluppi, Gianluca; Salizzoni, Mauro; Marsoni, Silvia; Kragh, Michael; Lantto, Johan; Cassingena, Andrea; Li, Qing Kay; Karchin, Rachel; Scharpf, Robert; Sartore-Bianchi, Andrea; Siena, Salvatore; Diaz, Luis A.; Trusolino, Livio; Velculescu, Victor E.

In: Nature, Vol. 526, No. 7572, 08.10.2015, p. 263-267.

Research output: Contribution to journalArticle

Bertotti, A, Papp, E, Jones, S, Adleff, V, Anagnostou, V, Lupo, B, Sausen, M, Phallen, J, Hruban, CA, Tokheim, C, Niknafs, N, Nesselbush, M, Lytle, K, Sassi, F, Cottino, F, Migliardi, G, Zanella, ER, Ribero, D, Russolillo, N, Mellano, A, Muratore, A, Paraluppi, G, Salizzoni, M, Marsoni, S, Kragh, M, Lantto, J, Cassingena, A, Li, QK, Karchin, R, Scharpf, R, Sartore-Bianchi, A, Siena, S, Diaz, LA, Trusolino, L & Velculescu, VE 2015, 'The genomic landscape of response to EGFR blockade in colorectal cancer' Nature, vol 526, no. 7572, pp. 263-267. DOI: 10.1038/nature14969
Bertotti A, Papp E, Jones S, Adleff V, Anagnostou V, Lupo B et al. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature. 2015 Oct 8;526(7572):263-267. Available from, DOI: 10.1038/nature14969
Bertotti, Andrea ; Papp, Eniko ; Jones, Siân ; Adleff, Vilmos ; Anagnostou, Valsamo ; Lupo, Barbara ; Sausen, Mark ; Phallen, Jillian ; Hruban, Carolyn A. ; Tokheim, Collin ; Niknafs, Noushin ; Nesselbush, Monica ; Lytle, Karli ; Sassi, Francesco ; Cottino, Francesca ; Migliardi, Giorgia ; Zanella, Eugenia R. ; Ribero, Dario ; Russolillo, Nadia ; Mellano, Alfredo ; Muratore, Andrea ; Paraluppi, Gianluca ; Salizzoni, Mauro ; Marsoni, Silvia ; Kragh, Michael ; Lantto, Johan ; Cassingena, Andrea ; Li, Qing Kay ; Karchin, Rachel ; Scharpf, Robert ; Sartore-Bianchi, Andrea ; Siena, Salvatore ; Diaz, Luis A. ; Trusolino, Livio ; Velculescu, Victor E./ The genomic landscape of response to EGFR blockade in colorectal cancer. In: Nature. 2015 ; Vol. 526, No. 7572. pp. 263-267
@article{00130bec069b4d31b8298c2ac5140abb,
title = "The genomic landscape of response to EGFR blockade in colorectal cancer",
abstract = "Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.",
author = "Andrea Bertotti and Eniko Papp and Si\{^a}n Jones and Vilmos Adleff and Valsamo Anagnostou and Barbara Lupo and Mark Sausen and Jillian Phallen and Hruban, {Carolyn A.} and Collin Tokheim and Noushin Niknafs and Monica Nesselbush and Karli Lytle and Francesco Sassi and Francesca Cottino and Giorgia Migliardi and Zanella, {Eugenia R.} and Dario Ribero and Nadia Russolillo and Alfredo Mellano and Andrea Muratore and Gianluca Paraluppi and Mauro Salizzoni and Silvia Marsoni and Michael Kragh and Johan Lantto and Andrea Cassingena and Li, {Qing Kay} and Rachel Karchin and Robert Scharpf and Andrea Sartore-Bianchi and Salvatore Siena and Diaz, {Luis A.} and Livio Trusolino and Velculescu, {Victor E.}",
year = "2015",
month = "10",
day = "8",
doi = "10.1038/nature14969",
language = "English (US)",
volume = "526",
pages = "263--267",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7572",

}

TY - JOUR

T1 - The genomic landscape of response to EGFR blockade in colorectal cancer

AU - Bertotti,Andrea

AU - Papp,Eniko

AU - Jones,Siân

AU - Adleff,Vilmos

AU - Anagnostou,Valsamo

AU - Lupo,Barbara

AU - Sausen,Mark

AU - Phallen,Jillian

AU - Hruban,Carolyn A.

AU - Tokheim,Collin

AU - Niknafs,Noushin

AU - Nesselbush,Monica

AU - Lytle,Karli

AU - Sassi,Francesco

AU - Cottino,Francesca

AU - Migliardi,Giorgia

AU - Zanella,Eugenia R.

AU - Ribero,Dario

AU - Russolillo,Nadia

AU - Mellano,Alfredo

AU - Muratore,Andrea

AU - Paraluppi,Gianluca

AU - Salizzoni,Mauro

AU - Marsoni,Silvia

AU - Kragh,Michael

AU - Lantto,Johan

AU - Cassingena,Andrea

AU - Li,Qing Kay

AU - Karchin,Rachel

AU - Scharpf,Robert

AU - Sartore-Bianchi,Andrea

AU - Siena,Salvatore

AU - Diaz,Luis A.

AU - Trusolino,Livio

AU - Velculescu,Victor E.

PY - 2015/10/8

Y1 - 2015/10/8

N2 - Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

AB - Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

UR - http://www.scopus.com/inward/record.url?scp=84944079826&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944079826&partnerID=8YFLogxK

U2 - 10.1038/nature14969

DO - 10.1038/nature14969

M3 - Article

VL - 526

SP - 263

EP - 267

JO - Nature

T2 - Nature

JF - Nature

SN - 0028-0836

IS - 7572

ER -