Cancer Genetics and Epigenetics, 2025, Vol.13, No.1, 41-49 http://medscipublisher.com/index.php/cge 44 In addition to single gene modification, researchers are attempting to combine CRISPR technology with existing therapies. Studies show that knocking out specific genes can significantly enhance the response of cancer cells to targeted drugs and chemotherapy drugs. This combined therapy not only expands the range of therapeutic targets, but also opens up new ways to improve the efficacy of existing drugs (Wang et al., 2017; Valashedi et al., 2022). 4 The Application of CRISPR/Cas9 in HER2-Positive Breast Cancer 4.1 The tumor-suppressing effect of targeted knockout of HER2 gene CRISPR gene editing technology has been successfully applied to specifically silence the HER2 gene in breast cancer cells and significantly inhibit tumor progression. By designing guide RNA to target the key exons of the HER2 gene, the research team achieved proliferation inhibition in HER2-amplified cancer cells. This intervention strategy induces the generation of dominant negative mutations while blocking cell growth, interfering with downstream signal networks such as MAPK/ERK. Its mode of action is different from that of conventional therapies such as Herceptin (Wang and Sun, 2017). Single-cell sequencing data show that HER2 inactivation triggers the remodeling of the gene expression network, providing an important basis for understanding the malignant mechanism of tumors and developing new drugs. CRISPR-mediated HER2 functional silencing can alter the gene activity of cancer cells and promote therapeutic innovation. In some breast cancer models, knocking out HER2 causes molecular alterations related to the decline in tumor invasiveness and new therapeutic targets are discovered (Wang et al., 2017; Wang, 2024). This proves that CRISPR has a dual role in both basic research and therapeutic development. 4.2 Precise regulation of drug resistance pathways by CRISPR CRISPR technology plays an important role in studying the drug resistance mechanism of HER2-positive breast cancer, especially showing unique advantages in the research of PI3K/AKT and PTEN-related pathways. The overactivity of these signaling pathways often leads to drug failure and deterioration of the condition. Precise regulation of key targets through CRISPR can effectively inhibit drug resistance and improve therapeutic effects (Chen et al., 2018). Research has confirmed that adjusting the core genes of the PI3K pathway can enhance the sensitivity of HER2-targeted drugs, while CRISPR gene modification technology can reactivate the drug effect (Ferraro et al., 2023). This technology can not only analyze the molecular mechanism of drug resistance, but also lay the technical support for personalized treatment. By locating and correcting the key mutations of the PI3K/AKT-PTEN pathway, CRISPR can formulate therapies that better match the patient's condition, thereby improving the therapeutic effect and delaying the occurrence of drug resistance (Chen et al., 2018; Ferraro et al., 2023). This treatment strategy based on genetic characteristics highlights the significant value of CRISPR in overcoming tumor drug resistance. 4.3 Attempts at the application of multi-pathway collaborative intervention CRISPR, when combined with existing treatment methods, shows good complementarity. Experimental data show that the editing of HER2-related genes, when used in combination with PARP inhibitors, can produce enhanced anti-cancer effects, bringing new inspirations to clinical treatment (Wang and Sun, 2017). This combined model can not only enhance the treatment level of traditional therapies, but also provide more possibilities for dealing with drug resistance problems. Meanwhile, integrating the CRISPR system into immunotherapy and targeted therapy can construct a more complete combined intervention framework. By modifying immune-related genes or enhancing the expression of drug targets, this technology can improve the ability of immune cells to recognize and attack tumors. Combined with the precise strike effect of targeted drugs, this scheme is expected to achieve a more lasting therapeutic response (Ferraro et al., 2023; Liu et al., 2024). This multi-target and collaborative treatment concept fully demonstrates the flexibility of CRISPR and brings a new direction for solving the treatment problems of breast cancer.
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