Patient-Derived Xenografts and Matched Cell Lines Identify Pharmacogenomic Vulnerabilities in Colorectal Cancer.
Adult
Aged
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Biomarkers, Tumor
/ genetics
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cohort Studies
Colon
/ pathology
Colorectal Neoplasms
/ genetics
Drug Resistance, Neoplasm
/ genetics
Female
Gene Dosage
Humans
Lapatinib
/ pharmacology
Male
Mice
Microsatellite Instability
Middle Aged
Precision Medicine
Primary Cell Culture
RNA-Seq
Rectum
/ pathology
Trastuzumab
/ pharmacology
Treatment Outcome
Werner Syndrome Helicase
/ genetics
Exome Sequencing
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
received:
20
10
2018
revised:
13
06
2019
accepted:
29
07
2019
pubmed:
4
8
2019
medline:
22
9
2020
entrez:
4
8
2019
Statut:
ppublish
Résumé
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 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 The XL platform represents a preclinical tool for functional gene validation and proof-of-concept studies to identify novel druggable vulnerabilities in colorectal cancer.
Identifiants
pubmed: 31375513
pii: 1078-0432.CCR-18-3440
doi: 10.1158/1078-0432.CCR-18-3440
pmc: PMC7611232
mid: EMS128728
doi:
Substances chimiques
Biomarkers, Tumor
0
Lapatinib
0VUA21238F
WRN protein, human
EC 3.6.4.12
Werner Syndrome Helicase
EC 3.6.4.12
Trastuzumab
P188ANX8CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6243-6259Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : European Research Council
ID : 724748
Pays : International
Organisme : Wellcome Trust
ID : 206194
Pays : United Kingdom
Informations de copyright
©2019 American Association for Cancer Research.
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