Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer

Luca Lazzari, Giorgio Corti, Gabriele Picco, Claudio Isella, Monica Montone, Pamela Arcella, Erika Durinikova, Eugenia R Zanella, Luca Novara, Fabiane Barbosa, Andrea Cassingena, Carlotta Cancelliere, Enzo Medico, Andrea Sartore-Bianchi, Salvatore Siena, Mathew J Garnett, Andrea Bertotti, Livio Trusolino, Federica Di Nicolantonio, Michael LinnebacherAlberto Bardelli, Sabrina Arena

Research output: Contribution to journalArticle

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, XL), derived from PDXs of colorectal cancer 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 colorectal cancer 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.

CONCLUSIONS: The XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.

Original languageEnglish
Pages (from-to)6243-6259
Number of pages17
JournalClin. Cancer Res.
Volume25
Issue number20
DOIs
Publication statusPublished - Oct 15 2019

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