Colorectal cancer consensus molecular subtypes translated to preclinical models uncover potentially targetable cancer cell dependencies
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Abstract
Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression–based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell–intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities. Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell–adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model. Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. Clin Cancer Res; 24(4); 794–806. ©2017 AACR.
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HSP90, PAK2, and AKT3 have emerged as candidate targets from preclinical studies of CMS4 colorectal cancer.
“Other candidate targets have emerged from preclinical studies, including HSP90, combined with 5-FU (7), PAK2 (67) or AKT3 (42)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [7]
Luminespib combined with 5-FU reduced tumor growth in preclinical models of CMS4 colorectal cancer.
“| HSP90 | Luminespib + 5-FU | Reduced tumor growth | (7) |”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [7]
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- Authors
- Sveen, A., Bruun, J., Eide, P. W., Eilertsen, I. A., Ramirez, L., Murumägi, A., Arjama, M., Danielsen, S. A., Kryeziu, K., Elez, E., Tabernero, J., Guinney, J., Palmer, H. G., Nesbakken, A., Kallioniemi, O., Dienstmann, R., & Lothe, R. A.
- Affiliations
- Oslo University Hospital (NO)
- Universitat Autònoma de Barcelona (ES)
- University of Helsinki (FI)
- 4Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain.
- Sage Bionetworks (US)
- Corresponding author
- Lothe, Ragnhild A.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2018-02-14
- Volume
- 24
- Issue
- 4
- Pages
- 794-806
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2771952185
- Cited by
- 256
- References
- 50
- Citations by year
- 2026: 23 · 2025: 12 · 2024: 19 · 2023: 36 · 2022: 32 · 2021: 48 · 2020: 38 · 2019: 31 · 2018: 17
- FWCI
- 10.37
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- Kreftforeningen (Norwegian Cancer Society) (6824048-2016, 182759-2016)
- Ministry of Health and Care Services | Helse Sør-Øst RHF (Southern and Eastern Norway Regional Health Authority)
- Stiftelsen Kristian Gerhard Jebsen (Stiftelsen KGJ)
- Research Council of Norway (250993)
- Merck KGaA
- European Union Seventh Framework Programme (609020)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- colorectal cancer, consensus molecular subtypes, patient-derived xenografts, drug repurposing, drug sensitivity profiling, Hsp90 inhibitors, EGFR inhibitors, HER2 inhibitors, microsatellite instability, mesenchymal phenotype, chemoresistance, 5-fluorouracil, combination therapy
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Cell Survival, Fluorouracil, Humans, Isoxazoles, Mice, Nude, Resorcinols, Biomarkers, Tumor, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Mice, SCID, Gene Expression Profiling, Xenograft Model Antitumor Assays, Consensus, Cell Line, Tumor
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