Chemogenomic profiling of breast cancer patient-derived xenografts reveals targetable vulnerabilities for difficult-to-treat tumors.
Animals
Breast Neoplasms
/ drug therapy
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
/ methods
Female
Gene Expression Regulation, Neoplastic
Humans
Mice, Inbred NOD
Mutation
Precision Medicine
Prognosis
Proof of Concept Study
Protein Array Analysis
/ methods
Whole Genome Sequencing
Xenograft Model Antitumor Assays
/ methods
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
16 06 2020
16 06 2020
Historique:
received:
08
12
2019
accepted:
26
05
2020
entrez:
18
6
2020
pubmed:
18
6
2020
medline:
24
6
2021
Statut:
epublish
Résumé
Subsets of breast tumors present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare histologies. Here, we developed 37 patient-derived xenografts (PDX) from these difficult-to-treat cancers to interrogate their molecular composition and functional biology. Whole-genome and transcriptome sequencing and reverse-phase protein arrays revealed that PDXs conserve the molecular landscape of their corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset of models displayed high rates of dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling was performed in vivo with standard-of-care agents, where multi-drug chemoresistance was retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features in the majority of PDXs, and marked regressions were observed in a subset that was evaluated in vivo. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for preclinical studies on difficult-to-treat breast tumors.
Identifiants
pubmed: 32546838
doi: 10.1038/s42003-020-1042-x
pii: 10.1038/s42003-020-1042-x
pmc: PMC7298048
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
310Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : CIHR
Pays : Canada
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