Correcting TP53 Mutations in Colorectal Cancer: Can Prime Editing Fill the Gap in Precision Oncology?
Background
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, and its genetic heterogeneity and resistance to treatment continue to result in poor outcomes for advanced patients. In particular, mutations in the tumor suppressor gene TP53 are found in 40-60% of colorectal cancer patients and are considered a key molecular event that simultaneously disrupts genome stability and promotes tumor progression.
Conventional CRISPR-Cas9-based gene editing necessarily involves double-strand DNA breaks (DSBs). DSBs are repaired via the non-homologous end-joining (NHEJ) pathway, which can lead to unintended insertions and deletions (indels), and in environments where DNA repair mechanisms are already compromised, such as in tumor cells, this can pose a significant risk of additional genomic instability. This makes it difficult to apply conventional methods to targets that require precise editing at the single-base level, such as TP53. Prime editing is gaining attention as a next-generation tool to bridge this gap.
Key Findings
This review systematically analyzes literature published between 2010 and 2026 in PubMed, Scopus, Web of Science, and Google Scholar to comprehensively examine the potential of prime editing to correct TP53 mutations.
Prime editing is a 'search-and-replace' system consisting of a Cas9 nickase, a reverse transcriptase fusion protein, and a prime editing guide RNA (pegRNA). By introducing only a single-strand nick without DSBs, it significantly reduces the rate of indel formation compared to conventional CRISPR-Cas9 and allows for the programming of both point mutations and small insertions/deletions. The recently developed Prime Editor Max (PE Max) further improves editing efficiency by optimizing the nuclear localization signal and engineering the reverse transcriptase.
The review particularly highlights the intersection of TP53 hotspot mutations and prime editing. Common missense mutations in colorectal cancer, such as R175H, R248W, and R273H, can be restored to their wild-type form through single-base substitutions, which aligns perfectly with the editing capabilities of prime editing. With accumulating evidence of correction in organoid models, preclinical pipelines to confirm functional restoration at the patient-derived tissue level are also emerging.
However, the review also clearly identifies practical barriers. Efficient delivery to tumor tissue, immunogenicity, off-target editing frequency, and achieving sufficient editing efficiency in vivo are all challenges that must be addressed before clinical translation.
Significance and Prospects
This review is significant in that it integrates TP53 hotspot biology, advances in prime editing technology, and CRC-specific translational research challenges into a single framework. In particular, the presentation of a step-by-step roadmap from pegRNA design for each mutation to organoid validation and clinical application provides practical reference material for future researchers.
However, there are still many hurdles to overcome before prime editing-based precision oncology can reach actual patients. The tumor-targeting efficiency of lipid nanoparticle (LNP) or viral vector-based delivery platforms is not yet sufficient, and there is a lack of long-term safety data for edited cells. It is also unclear whether sufficient numbers of tumor cells can be edited while evading immune surveillance. Ultimately, a comparative study is needed to determine whether an ex vivo editing and re-implantation strategy or an in vivo direct editing strategy is more suitable for colorectal cancer.
Prime editing is undoubtedly a promising tool for precision oncology, but the work of bridging the gap between technological optimism and clinical reality is just beginning.
BACKGROUND: Colorectal cancer (CRC) is a major global health concern, with high mortality due to genetic heterogeneity and resistance to treatment. Tumor Protein p53 (TP53) mutations are also among the most important molecular changes that can disrupt genomic stability and facilitate tumor progression, so it is a critical target for precision-based interventions. AIM: This review aims to discuss the future potential of prime editing as a new generation of genome engineering to identify precise approaches to correct TP53 mutations in colorectal cancer. METHOD: A focused literature review was conducted on PubMed, Scopus, Web of Science, and Google Scholar for articles published between the years of 2010 and 2026. The keywords used in the search were CRC, TP53 mutation, prime editing, Prime Editing Guide RNA (pegRNA), CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9), and precision oncology. Studies were screened for experimental, mechanistic, and translational, and the focus was on mutation-specific editing, delivery platforms, organoid validation, clinically relevant barriers, etc. RESULTS/DISCUSSION: Prime editing is a programmable search-and-replace method that does not involve two single-stranded Deoxyribonucleic Acid (DNA) breaks, resulting in fewer Insertions/deletions (indels) and greater precision compared with traditional CRISPR-Cas9 approaches. Recent systems like Prime Editor Max (PE CONCLUSION: Precision oncology with prime editing has the potential to be a useful tool for CRC, though optimized delivery, thorough preclinical testing, and safety monitoring will be required for therapeutic adoption. ORIGINALITY: This review combines TP53 hotspot biology, recent breakthroughs in prime editing technology, and CRC-specific translational challenges, and provides a step-by-step approach to its clinical application in a unique way.
Although colorectal cancer has diverse treatment options, including surgery, chemotherapy, targeted therapy, and immune checkpoint inhibitors, tumors with TP53 mutations exhibit high chemoresistance and poor prognosis. If prime editing can restore the wild-type function of TP53, it could open up new strategies for patients who do not respond to existing treatments.
In the short term, the most realistic application scenario is to combine it with drug sensitivity screening in patient-derived organoids to investigate whether TP53 correction can restore sensitivity to specific anticancer drugs. In the medium to long term, the strategy could be extended to other cancers with frequent TP53 mutations, such as pancreatic cancer and ovarian cancer, and could serve as an early model for prime editing-based companion diagnostics and therapeutics.