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.

The genomic landscape of response to EGFR blockade in colorectal cancer

BERTOTTI, Andrea
Co-first
;
LUPO, Barbara;SASSI, FRANCESCO;MIGLIARDI, GIORGIA;ZANELLA, Eugenia Rosalinda;RUSSOLILLO, NADIA;MELLANO, Alfredo;SALIZZONI, Mauro;TRUSOLINO, Livio
Co-last
;
2015

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.
526
7572
263
267
http://www.nature.com/nature/index.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878148/
Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; DNA Copy Number Variations; Drug Resistance, Neoplasm; Exome; Female; Genome, Human; Humans; Insulin Receptor Substrate Proteins; MAP Kinase Kinase 1; Mice; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins p21(ras); Receptor, Epidermal Growth Factor; Receptor, ErbB-2; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor alpha; Xenograft Model Antitumor Assays; Genomics; Multidisciplinary
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*. (*Co-Senior e Corresponding Authors)
File in questo prodotto:
File Dimensione Formato  
2015_The genomic landscape of response to EGFR blockade in colorectal cancer.pdf

Accesso riservato

Descrizione: Bertotti et al_2015_Nature_RISERVATO
Tipo di file: PDF EDITORIALE
Dimensione 5.57 MB
Formato Adobe PDF
5.57 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Bertotti et al_nature_2015.pdf

Accesso aperto con embargo fino al 09/10/2016

Descrizione: Bertotti et al_2015_Nature_APERTO
Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 913.27 kB
Formato Adobe PDF
913.27 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1559157
Citazioni
  • ???jsp.display-item.citation.pmc??? 193
  • Scopus 293
  • ???jsp.display-item.citation.isi??? 284
social impact