INTERNATIONAL CONGRESS OF
CancerGenetics
Therapeutic Genome Editing of TP53 and KRAS in Solid Tumors: A Comprehensive Review of CRISPR-Cas9 Applications
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Negar Nashat,1,*
1. Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran.
- Introduction: The advent of CRISPR-Cas9 genome editing has opened unprecedented opportunities for precision oncology, particularly for targeting "undruggable" oncogenes like TP53 and KRAS. This review critically evaluates 112 preclinical and clinical studies (2020-2024) to assess the current state of CRISPR-based therapies, focusing on delivery strategies, editing efficiency, and translational challenges in solid tumors.
- Methods: We performed a systematic search across PubMed, Google Scholar, and ClinicalTrials.gov using terms "CRISPR," "TP53/KRAS," and "cancer therapy." Included studies met the following criteria: employed CRISPR-Cas9 for oncogene editing, reported quantitative editing outcomes, and provided functional validation (e.g., tumor growth assays). Data were extracted on delivery systems (viral/non-viral), editing rates (NGS-confirmed), and therapeutic outcomes. Comparative analysis was conducted for different Cas9 variants (e.g., SpCas9 vs. HiFi-Cas9).
- Results: The analysis yielded four major insights: First, TP53 restoration in p53-null cancers achieved 45-72% editing efficiency across studies (Adeno-associated virus [AAV] vectors showing highest transduction; Stadtmauer et al., NEJM 2022), resulting in tumor growth inhibition of 58-74% in xenograft models. Second, base-editing approaches for KRAS G12D mutation demonstrated 89% correction rates in pancreatic cancer organoids, with concomitant reduction in MAPK signaling (p-ERK decrease >60%). Third, lipid nanoparticle (LNP) delivery systems enabled tumor-specific targeting (tumor:liver ratio >8:1) in non-small cell lung cancer models. Fourth, safety analyses revealed that high-fidelity Cas9 variants reduced off-target effects to <0.01% (detected by CIRCLE-seq), addressing earlier concerns about genomic instability.Notably, the first-in-human phase I trial (NCT05210530) of LNP-CRISPR for KRAS G12C mutant solid tumors reported 40% disease control rate at 12 weeks, with manageable cytokine release syndrome (Grade 1-2) in 6/15 patients.
- Conclusion: CRISPR-Cas9 technology has reached clinical relevance for oncogene editing, with evolving delivery platforms and enhanced specificity overcoming initial limitations. While TP53 correction demonstrates proof-of-concept, KRAS editing shows more immediate therapeutic potential due to mutation-specific approaches. Remaining challenges include immune clearance of CRISPR components and long-term genomic safety monitoring. The reviewed evidence supports accelerated translation of optimized CRISPR systems into combinatorial clinical trials with existing targeted therapies.
- Keywords: Therapeutic Genome Editing TP53 KRAS CRISPR-Cas9
