Purpose Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGF Receptor (EGFR) antibody cetuximab, and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies. Experimental Design. Xenospheres underwent exome-sequencing analysis, gene expression profile and in vitro targeted treatments to assess genetic, biological and pharmacological correspondence with xenopatients, and to investigate non-genetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model. Results. Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo, generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition. Conclusions. Xenospheres are a reliable model to identify both genetic and non-genetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response.

A molecularly annotated model of patient-derived colon cancer stem-like cells to assess genetic and non-genetic mechanisms of resistance to anti-EGFR therapy

Luraghi, Paolo;Bigatto, Viola;CIPRIANO, ELIA;Reato, Gigliola;Orzan, Francesca;Sassi, Francesco;De Bacco, Francesca;Isella, Claudio;Bellomo, Sara Erika;Medico, Enzo;Comoglio, Paolo M;Bertotti, Andrea;Trusolino, Livio;Boccaccio, Carla
Last
2018

Abstract

Purpose Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGF Receptor (EGFR) antibody cetuximab, and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies. Experimental Design. Xenospheres underwent exome-sequencing analysis, gene expression profile and in vitro targeted treatments to assess genetic, biological and pharmacological correspondence with xenopatients, and to investigate non-genetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model. Results. Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo, generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition. Conclusions. Xenospheres are a reliable model to identify both genetic and non-genetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response.
24
4
807
820
http://clincancerres.aacrjournals.org/content/24/4/807.long
COLORECTAL-CANCER; PRECISION MEDICINE; KINASE INHIBITORS; TUMOR-GROWTH; CETUXIMAB; EVOLUTION; AMPLIFICATION; SENSITIVITY; ACTIVATION; BIOMARKERS
Luraghi, Paolo; Bigatto, Viola; Cipriano, Elia; Reato, Gigliola; Orzan, Francesca; Sassi, Francesco; De Bacco, Francesca; Isella, Claudio; Bellomo, Sara Erika; Medico, Enzo; Comoglio, Paolo M; Bertotti, Andrea; Trusolino, Livio; Boccaccio, Carla
File in questo prodotto:
File Dimensione Formato  
A molecularly.pdf

Accesso riservato

Descrizione: Clin Canc Res 2017_RISERVATO
Tipo di file: PDF EDITORIALE
Dimensione 1.85 MB
Formato Adobe PDF
1.85 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Luraghi et al._Text_CCR-17-1251R1_postprint_full.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 8.86 MB
Formato Adobe PDF
8.86 MB 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/2318/1662775
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 17
social impact