title: Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease.
abstract: Effective treatment options for advanced colorectal cancer (CRC) are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established 'driver' lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs) of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts.
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Belmont
authors.affiliation: Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic. Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Budinska
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Sinnamon
authors.affiliation: Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Coffee
authors.affiliation: Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, G61 1BD, UK.
authors.forename: Sahra
authors.initials: S
authors.lastname: Derkits
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, G61 1BD, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: University Hospital Gasthuisberg, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Pfizer Biotherapeutics Clinical Research, Cambridge, 02140 MA, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, San Diego, CA 92121, USA. esmartin.phd@gmail.com.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Martin
mesh_terms: D000483:Alleles; D000818:Animals; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D011905:Genes, ras; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013045:Species Specificity
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
keywords: BRAF; Colorectal cancer; GEMM; Genomic signatures; KRAS; MAPK
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