CRISPR Gene Editing Strategies for Targeting Oncogene Addiction in Colorectal Cancer

Abstract

Background: Oncogene addiction occurs in most tumour cells it is a phenomenon capable of driving colorectal cancer (CRC) growth, where tumour cells rely on genes like KRAS, BRAF, or MYC to survive. This has been so far seen as an exploitable target for precision therapies. Aim: This review examines how CRISPR-based gene editing strategies can be used to disrupt oncogene addiction in CRC, with a keen focus on their therapeutic potential. Methodology: A systematic review of recent studies, retrieved from reputable databases including PubMed and Google Scholar was conducted. Data from CRISPR/Cas9 and other CRISPR-based applications targeting key oncogenes in CRC models were collected. Findings Results: Findings show that CRISPR/Cas9-mediated knockout of specific oncogenes such as mutations of KRAS or BRAF were able to disrupt tumour-dependent MAPK/ERK signalling, reducing tumour growth in 60–80% of preclinical CRC models. Other innovative CRISPR-stimulated applications like Base editing showed efficacy in correcting specific mutations like KRAS G12D, restoring normal gene function, while prime editing addresses complex mutations with high precision, achieving high efficiency in organoids. CRISPR interference (CRISPRi) downregulates MYC expression without permanent DNA changes, inhibiting proliferation in CRC cell lines. Combining CRISPR with small molecule inhibitors, such as MEK inhibitors, enhances tumour suppression by 30–50% in mouse models by targeting compensatory pathways. Additionally, CRISPR-edited tumour-infiltrating lymphocytes (TILs) improve immunotherapy responses in early-phase trials (e.g., NCT04426669). However, challenges reported include off-target edits, which occur in 5–10% of CRISPR/Cas9 applications, and poor delivery to solid CRC tumours due to dense stroma. Tumour heterogeneity complicates targeting, as subpopulations may rely on different oncogenes. Ethical concerns and regulatory hurdles, such as ensuring safety and equitable access still needs to be addressed before clinical translation. Conclusion: Ongoing studies are exploring high-fidelity CRISPR variants and tumour-targeted nanoparticles to improve specificity and delivery. Innovative next-generation tools are being explored, like Cas13 for RNA editing, integration with liquid biopsies for personalized mutation targeting, and combining CRISPR with immunotherapies to overcome resistance. These advancements position CRISPR as a promising approach to revolutionize CRC treatment by precisely targeting oncogene addiction, provided delivery and safety challenges are addressed.