• CRISPR-Mediated Silencing of Oncogenes: A Promising Frontier in Targeted Cancer Therapy
  • Neda Zahmatkesh,1,*
    1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.


  • Introduction: Cancer develops through a complex interaction of genetic and epigenetic alterations, with oncogenes playing a pivotal role in driving uncontrolled cell growth and tumor progression. Traditional treatments like chemotherapy and radiotherapy, while commonly used, often lack specificity and can cause serious side effects due to damage to healthy tissues. Recent breakthroughs in gene-editing technologies—especially CRISPR-Cas9—have introduced the possibility of selectively disabling oncogenes, offering a more targeted and potentially less toxic approach to cancer therapy. This review aims to explore recent progress in CRISPR-mediated oncogene disruption, examining the methodologies used, key preclinical findings, and the therapeutic potential of this strategy across various cancer types.
  • Methods: To conduct this review, a comprehensive literature search was carried out using databases such as PubMed, Scopus, Web of Science, and Google Scholar. The search focused on publications from 2018 to 2025 and included keywords like “CRISPR-Cas9,” “oncogene knockout,” “gene editing in cancer,” “KRAS silencing,” “MYC CRISPR inhibition,” and “gene therapy.” Only peer-reviewed sources—including original research articles, meta-analyses, and high-impact reviews—were included. From an initial pool of 74 studies, 40 of the most relevant publications were selected for in-depth analysis, focusing on therapeutic targets, experimental strategies, and clinical relevance.
  • Results: The CRISPR-Cas9 system enables precise gene editing by creating double-strand breaks (DSBs) at specific DNA sequences. These breaks are typically repaired through non-homologous end joining (NHEJ), often resulting in mutations that disrupt gene function. This mechanism has been effectively used to knock out key oncogenes in experimental cancer models. One prominent target is KRAS, a gene commonly mutated in pancreatic, colorectal, and lung cancers. CRISPR-based disruption of KRAS has shown the ability to suppress tumor growth and improve responsiveness to chemotherapy. Another critical gene, MYC, a central regulator of cell proliferation, has been silenced in models of Burkitt lymphoma and triple-negative breast cancer, leading to reduced cell division and increased apoptosis. Similarly, targeting BCL2 (in leukemia) and EGFR (in lung cancer) using CRISPR has demonstrated reduced cell viability and metastatic capacity. To enhance in vivo delivery and editing precision, several strategies—such as lipid nanoparticles, adeno-associated virus (AAV) vectors, and exosome-based systems—have been developed. Moreover, some studies employed CRISPR interference (CRISPRi) using a deactivated Cas9 (dCas9) fused with a KRAB repressor domain to epigenetically suppress gene expression. This method inhibits transcription without causing DNA breaks, thus reducing the risk of off-target effects. Despite these advances, several challenges remain. Immune reactions to Cas9 protein, unintended edits at non-target sites, and tumor heterogeneity can complicate therapeutic outcomes. Nevertheless, combinatorial approaches—such as simultaneous silencing of MYC and BCL2—have shown increased antitumor effects, indicating the potential of multi-target strategies.
  • Conclusion: CRISPR-Cas9 technology represents a transformative tool in cancer research and therapy, offering precise, gene-specific interventions that may overcome the limitations of conventional treatments. The targeted disruption of oncogenes has opened new possibilities for developing more effective and less toxic cancer therapies. As advances continue in refining delivery systems, enhancing editing accuracy, and managing immunogenicity, CRISPR is moving closer to clinical application. Future directions may involve personalized gene-editing protocols tailored to individual tumors, integration with immunotherapy or conventional drugs, and ultimately, incorporation into standard oncology care.
  • Keywords: CRISPR-Cas9, Oncogene Silencing, Cancer Gene Therapy, KRAS