Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts

Umberto Perron, Elena Grassi, Aikaterini Chatzipli, Marco Viviani, Emre Karakoc, Lucia Trastulla, Lorenzo M. Brochier, Claudio Isella, Eugenia R. Zanella, Hagen Klett, Ivan Molineris, Julia Schueler, Manel Esteller, Enzo Medico, Nathalie Conte, Ultan McDermott, Livio Trusolino (), Andrea Bertotti () and Francesco Iorio ()
Additional contact information
Umberto Perron: Human Technopole
Elena Grassi: Candiolo Cancer Institute FPO IRCCS
Aikaterini Chatzipli: Wellcome Sanger Institute, Wellcome Genome Campus
Marco Viviani: Candiolo Cancer Institute FPO IRCCS
Emre Karakoc: Wellcome Sanger Institute, Wellcome Genome Campus
Lucia Trastulla: Human Technopole
Lorenzo M. Brochier: Human Technopole
Claudio Isella: Candiolo Cancer Institute FPO IRCCS
Eugenia R. Zanella: Candiolo Cancer Institute FPO IRCCS
Hagen Klett: Charles River Germany GmbH
Ivan Molineris: University of Torino
Julia Schueler: Charles River Germany GmbH
Manel Esteller: Badalona
Enzo Medico: Candiolo Cancer Institute FPO IRCCS
Nathalie Conte: European Molecular Biology Laboratory European Bioinformatics Institute
Ultan McDermott: Wellcome Sanger Institute, Wellcome Genome Campus
Livio Trusolino: Candiolo Cancer Institute FPO IRCCS
Andrea Bertotti: Candiolo Cancer Institute FPO IRCCS
Francesco Iorio: Human Technopole

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53163-y

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