ena-STUDY-Candiolo Cancer Institute-23-07-2019-12:58:09:592-881
Patient-derived xenografts and matched cell lines identify pharmacogenomic vulnerabilities in colorectal cancer
PURPOSE: Patient-derived xenograft (PDX) models accurately recapitulatethe tumor of origin in terms of histopathology, genomic landscape, andtherapeutic response, but some limitations due to costs associated with theirmaintenance 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 matchedpatient germline gDNA available.EXPERIMENTAL DESIGN: Whole exome and transcriptome sequencinganalyses were performed. Biomarkers of response and resistance to anti-HERtherapy were annotated. Dependency on the WRN helicase gene wasassessed in MSS, MSI-H and MSI-like XLs using a reverse geneticsfunctional approach.RESULTS: XLs recapitulated the entire spectrum of CRC transcriptionalsubtypes. Exome and RNA-seq analyses delineated several molecularbiomarkers of response and resistance to EGFR and HER2 blockade.Genotype-driven responses observed in vitro in XLs were confirmed in vivo inthe matched PDXs. MSI-H models were dependent upon WRN geneexpression, while loss of WRN did not affect MSS XLs growth. Interestingly,one MSS XL with transcriptional MSI-like traits was sensitive to WRNdepletion.CONCLUSION: The XL platform represents a preclinical tool for functionalgene validation and proof of concept studies to identify novel druggablevulnerabilities in CRC.
PURPOSE: Patient-derived xenograft (PDX) models accurately recapitulatethe tumor of origin in terms of histopathology, genomic landscape, andtherapeutic response, but some limitations due to costs associated with theirmaintenance 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 matchedpatient germline gDNA available.EXPERIMENTAL DESIGN: Whole exome and transcriptome sequencinganalyses were performed. Biomarkers of response and resistance to anti-HERtherapy were annotated. Dependency on the WRN helicase gene wasassessed in MSS, MSI-H and MSI-like XLs using a reverse geneticsfunctional approach.RESULTS: XLs recapitulated the entire spectrum of CRC transcriptionalsubtypes. Exome and RNA-seq analyses delineated several molecularbiomarkers of response and resistance to EGFR and HER2 blockade.Genotype-driven responses observed in vitro in XLs were confirmed in vivo inthe matched PDXs. MSI-H models were dependent upon WRN geneexpression, while loss of WRN did not affect MSS XLs growth. Interestingly,one MSS XL with transcriptional MSI-like traits was sensitive to WRNdepletion.CONCLUSION: The XL platform represents a preclinical tool for functionalgene validation and proof of concept studies to identify novel druggablevulnerabilities in CRC.