PURPOSE: Patient-derived xenograft (PDX) models accurately recapitulate the tumor of origin in terms of histopathology, genomic landscape, and therapeutic response, but some limitations due to costs associated with their maintenance and restricted amenability for large-scale screenings still exist. To overcome these issues, we established a platform of 2D cell lines (xeno-cell lines, XLs), derived from PDXs of colorectal cancer (CRC) with matched patient germline gDNA available. EXPERIMENTAL DESIGN: Whole exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the WRN helicase gene was assessed in MSS, MSI-H and MSI-like XLs using a reverse genetics functional approach. RESULTS: XLs recapitulated the entire spectrum of CRC transcriptional subtypes. Exome and RNA-seq analyses delineated several molecular biomarkers of response and resistance to EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XLs were confirmed in vivo in the matched PDXs. MSI-H models were dependent upon WRN gene expression, while loss of WRN did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to WRN depletion. CONCLUSION: The XL platform represents a preclinical tool for functional gene validation and proof of concept studies to identify novel druggable vulnerabilities in CRC.

Patient-derived xenografts and matched cell lines identify pharmacogenomic vulnerabilities in colorectal cancer

Isella C.;Arcella P.;Zanella E. R.;Cancelliere C.;Medico E.;Bertotti A.;Trusolino L.;Di Nicolantonio F.;Bardelli A.;Arena S.
2019

Abstract

PURPOSE: Patient-derived xenograft (PDX) models accurately recapitulate the tumor of origin in terms of histopathology, genomic landscape, and therapeutic response, but some limitations due to costs associated with their maintenance and restricted amenability for large-scale screenings still exist. To overcome these issues, we established a platform of 2D cell lines (xeno-cell lines, XLs), derived from PDXs of colorectal cancer (CRC) with matched patient germline gDNA available. EXPERIMENTAL DESIGN: Whole exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the WRN helicase gene was assessed in MSS, MSI-H and MSI-like XLs using a reverse genetics functional approach. RESULTS: XLs recapitulated the entire spectrum of CRC transcriptional subtypes. Exome and RNA-seq analyses delineated several molecular biomarkers of response and resistance to EGFR and HER2 blockade. Genotype-driven responses observed in vitro in XLs were confirmed in vivo in the matched PDXs. MSI-H models were dependent upon WRN gene expression, while loss of WRN did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to WRN depletion. CONCLUSION: The XL platform represents a preclinical tool for functional gene validation and proof of concept studies to identify novel druggable vulnerabilities in CRC.
25
20
6243
6259
https://clincancerres.aacrjournals.org/content/early/2019/08/02/1078-0432.CCR-18-3440
Colorectal cancer, preclinical models, EGFR, HER2, resistance
Lazzari L.; Corti G.; Picco G.; Isella C.; Montone M.; Arcella P.; Durinikova E.; Zanella E.R.; Novara L.; Barbosa F.; Cassingena A.; Cancelliere C.; Medico E.; Sartore-Bianchi A.; Siena S.; Garnett M.J.; Bertotti A.; Trusolino L.; Di Nicolantonio F.; Linnebacher M.; Bardelli A.; Arena S.
File in questo prodotto:
File Dimensione Formato  
Patient-derived xenografts and matched cell lines identify_pre.pdf

Accesso aperto

Tipo di file: PREPRINT (PRIMA BOZZA)
Dimensione 1.48 MB
Formato Adobe PDF
1.48 MB Adobe PDF Visualizza/Apri
6243.full.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 974.55 kB
Formato Adobe PDF
974.55 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

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/2318/1715076
Citazioni
  • ???jsp.display-item.citation.pmc??? 25
  • Scopus 30
  • ???jsp.display-item.citation.isi??? 30
social impact