The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efficient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the effectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efflux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of different cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the effectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.
The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.
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