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

Abstract

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. Whole-exome and transcriptome sequencing analyses were performed. Biomarkers of response and resistance to anti-HER therapy were annotated. Dependency on the <i>WRN</i> helicase gene was assessed in MSS, MSI-H, and MSI-like XLs using a reverse genetics functional approach. 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 <i>in vitro</i> in XLs were confirmed <i>in vivo</i> in the matched PDXs. MSI-H models were dependent upon <i>WRN</i> gene expression, while loss of <i>WRN</i> did not affect MSS XLs growth. Interestingly, one MSS XL with transcriptional MSI-like traits was sensitive to <i>WRN</i> depletion. The XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.