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Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants
Jasmin B Post1, Jeanine M L Roodhart2, Hugo J G Snippert1
1Molecular 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.
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.
Insights
Mutations in RAS and BRAF proteins drive colorectal cancer (CRC) and therapy resistance. This review explores their distinct roles in CRC, highlighting patient-derived organoids and genome editing for personalized treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RAS and BRAF proteins are frequently mutated in colorectal cancer (CRC), contributing to therapeutic resistance in metastatic cases.
- RAS isoforms are often viewed as redundant, but evidence suggests distinct oncogenic potentials and clinical outcomes for their mutant variants.
Purpose of the Study:
- To review the similarities and differences between RAS and BRAF oncogenes in colorectal cancer development, histology, and therapy resistance.
- To discuss the utility of patient-derived tumor organoids and genome editing in preclinical models for personalized therapy and understanding MAPK pathway mutations.
Main Methods:
- Literature review focusing on oncogenic RAS and BRAF mutations in CRC.
- Analysis of studies utilizing patient-derived tumor organoids for personalized therapy.
- Examination of genome editing techniques for CRC modeling in preclinical systems.
Main Results:
- Mutant RAS and BRAF variants exhibit differential oncogenic potentials and therapeutic implications in CRC.
- Patient-derived tumor organoids offer a platform for tailoring CRC treatments.
- Genome editing models elucidate the specific effects of MAPK pathway mutations on tumor growth and drug response.
Conclusions:
- Understanding the distinct roles of RAS and BRAF mutations is crucial for advancing CRC therapy.
- Advanced preclinical models like organoids and genome-edited systems are vital for developing personalized treatment strategies against CRC.
