Highlights
- •Organoids were obtained from 29 of 54 (53.7%) pancreatobiliary cancers.
- •Most of the organoids retained genotypes and histological phenotypes of primary tumours.
- •Exome sequencing unveiled diverse mutations in primary biliary tumours.
- •Organoids served for testing genotype-oriented targeted drug candidates.
Abstract
Background
Pancreatobiliary cancer is a highly aggressive tumour with a dismal prognosis. Personalised
medicine represents a promising and effective therapeutic approach for this intractable
disease. In this study, we aimed to establish a system for identifying and testing
genotype-oriented targeted drugs for pancreatobiliary cancers by combining exome sequencing
and organoid culture of primary tumours.
Methods
Tumour cells isolated from resected tumours were subjected to organoid cultures based
on published protocols with modifications. Exome sequencing was performed on the primary
tumours. Histopathological and molecular features of the primary tumours were validated
in the corresponding organoids. Genotype-oriented candidate targeted drugs were identified
from exome sequencing, and their efficacies were tested in the organoids.
Results
Organoid cultures succeeded in 30 of 54 (55.6%) cases. Six primary cancers of the
biliary tract and gall bladder were subjected to exome sequencing, which revealed
a variety of somatic mutations of genes involved in signalling pathways, epigenetic
modifiers, genome maintenance and metabolic enzymes. Most of the organoids of these
6 cases showed identical histopathological features and genomic aberrations as those
of the primary tumours. Some of the aberrations were candidates for targeted therapies.
Integrin-linked kinase (ILK) was one such candidate target, and an ILK inhibitor was confirmed to suppress proliferation
of patient-derived organoids.
Conclusions
By combining exome sequencing and organoid culture, our model enabled to identify
genotype-oriented targets for personalised medicine and to test efficacies of candidate
targeted drugs in the organoids. The current proof-of-concept approach could increase
therapeutic opportunities for patients with pancreatobiliary cancers.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: March 19, 2021
Accepted:
January 28,
2021
Received in revised form:
January 20,
2021
Received:
November 9,
2020
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
