Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants

Jasmin B Post; Jeanine M L Roodhart; Hugo J G Snippert

doi:10.1016/j.trecan.2019.12.005

Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants

Trends Cancer. 2020 Feb;6(2):111-129. doi: 10.1016/j.trecan.2019.12.005. Epub 2020 Jan 21.

Authors

Jasmin B Post¹, Jeanine M L Roodhart², Hugo J G Snippert³

Affiliations

¹ Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, CX Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands.
² Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands.
³ Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, CX Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands. Electronic address: H.J.G.Snippert@umcutrecht.nl.

PMID: 32061302
DOI: 10.1016/j.trecan.2019.12.005

Abstract

RAS and BRAF proteins are frequently mutated in colorectal cancer (CRC) and have been associated with therapy resistance in metastatic CRC patients. RAS isoforms are considered to act as redundant entities in physiological and pathological settings. However, there is compelling evidence that mutant variants of RAS and BRAF have different oncogenic potentials and therapeutic outcomes. In this review we describe similarities and differences between various RAS and BRAF oncogenes in CRC development, histology, and therapy resistance. In addition, we discuss the potential of patient-derived tumor organoids for personalized therapy, as well as CRC modeling using genome editing in preclinical model systems to study similarities and discrepancies between the effects of oncogenic MAPK pathway mutations on tumor growth and drug response.

Keywords: BRAF; CRC; RAS; organoids; targeted therapy.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Cell Culture Techniques
Cell Line, Tumor
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic
Humans
Mutation
Organoids / pathology*
Proto-Oncogene Proteins B-raf / genetics*
Xenograft Model Antitumor Assays / methods
ras Proteins / genetics*

Substances

Antineoplastic Agents
BRAF protein, human
Proto-Oncogene Proteins B-raf
ras Proteins