1. Molecular Subtyping Combined with Biological Pathway Analyses to Study Regorafenib Response in Clinically Relevant Mouse Models of Colorectal Cancer
- Author
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Matthias P. Ebert, Patrick Dicker, Livio Trusolino, Jochen H. M. Prehn, Adam Lafferty, Elodie Modave, Alice C. O’Farrell, Enzo Medico, Giorgia Migliardi, Niraj Khemka, Rodrigo Dienstmann, Evy Vanderheyden, Andrea Bertotti, Francesco Sassi, Claudio Isella, Eugenia R. Zanella, Diether Lambrechts, Guillem Argiles, Josep Tabernero, Manuela Salvucci, Annette T. Byrne, Johannes Betge, Luise Halang, Bram Boeckx, and Andreas U. Lindner
- Subjects
Cancer Research ,Pyridines ,Colorectal cancer ,Animals ,Biomarkers, Tumor ,Colorectal Neoplasms ,Disease Models, Animal ,Mice ,Phenylurea Compounds ,Treatment Outcome ,Xenograft Model Antitumor Assays ,Biology ,03 medical and health sciences ,Basal (phylogenetics) ,chemistry.chemical_compound ,0302 clinical medicine ,Regorafenib ,Gene expression ,medicine ,030304 developmental biology ,0303 health sciences ,Tumor ,Animal ,Reverse phase protein lysate microarray ,Cancer ,medicine.disease ,EPH receptor A2 ,Subtyping ,3. Good health ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Disease Models ,Cancer research ,Biomarkers - Abstract
Purpose: Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers. Experimental Design: Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment. Results: Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance. Conclusions: Subtype classification systems represent canonical “termini a quo” (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.
- Published
- 2021