Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts
Patient-derived xenografts (PDXs) are tumour fragments engrafted into mice for preclinical studies. PDXs offer clear advantages over simpler in vitro cancer models - such as cancer cell lines (CCLs) and organoids - in terms of structural complexity, heterogeneity, and stromal interactions. Here, we characterise 231 colorectal cancer PDXs at the genomic, transcriptomic, and epigenetic levels, along with their response to cetuximab, an EGFR inhibitor used clinically for metastatic colorectal cancer. After evaluating the PDXs' quality, stability, and molecular concordance with publicly available patient cohorts, we present results from training, interpreting, and validating the integrative ensemble classifier CeSta. This model takes in input the PDXs' multi-omic characterisation and predicts their sensitivity to cetuximab treatment, achieving an area under the receiver operating characteristics curve > 0.88. Our study demonstrates that large PDX collections can be leveraged to train accurate, interpretable drug sensitivity models that: (1) better capture patient-derived therapeutic biomarkers compared to models trained on CCL data, (2) can be robustly validated across independent PDX cohorts, and (3) could contribute to the development of future therapeutic biomarkers.
Authors
- Ivan Molineris (ORCID: https://orcid.org/0000-0003-2102-0804)
- Manel Esteller (ORCID: https://orcid.org/0000-0003-4490-6093)
- Marco Viviani (ORCID: https://orcid.org/0000-0003-4698-8870)
- Nathalie Conte (ORCID: https://orcid.org/0000-0002-1010-3121)
- Eugenia R. Zanella (ORCID: https://orcid.org/0000-0002-8036-3789)
- Emre Karakoç (ORCID: https://orcid.org/0000-0002-2324-8127)
- Hagen Klett (ORCID: https://orcid.org/0000-0001-7329-9048)
- Andrea Bertotti (ORCID: https://orcid.org/0000-0001-8196-7608)
- Lucia Trastulla (ORCID: https://orcid.org/0000-0001-8749-475X)
- Livio Trusolino (ORCID: https://orcid.org/0000-0002-6379-3365)
- Elena Grassi (ORCID: https://orcid.org/0000-0003-1066-927X)
- Enzo Médico (ORCID: https://orcid.org/0000-0002-3917-2438)
- Aikaterini Chatzipli (ORCID: https://orcid.org/0000-0003-4775-3846)
- Ultan McDermott (ORCID: https://orcid.org/0000-0001-9032-4700)
- Claudio Isella (ORCID: https://orcid.org/0000-0003-0679-4756)
- Francesco Iorio (ORCID: https://orcid.org/0000-0001-7063-8913)
- Umberto Perron (ORCID: https://orcid.org/0000-0001-8003-6545)
- Julia Schueler
- Lorenzo M Brochier (ORCID: https://orcid.org/0009-0002-5306-094X)
Institutions
- Sinopec (China) (CN)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Boston Children's Hospital (US)
- European Bioinformatics Institute (GB)
- Harvard University (US)
- Wellcome Sanger Institute (GB)
- Open Targets (GB)
- Josep Carreras Leukaemia Research Institute (ES)
- AstraZeneca (Singapore) (SG)
- Human Technopole (IT)
- Charles River Laboratories (Germany) (DE)
- Nerviano Medical Sciences (IT)
- Candiolo Cancer Institute (IT)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University of Turin (IT)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1038/s41467-024-53163-y
- Citations
- 10
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.83
Funders
- Cancer Research UK
- European Commission
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Horizon 2020 Framework Programme