Multiple pathogenic single-nucleotide polymorphisms (SNPs) have been identified as contributing factors in the aggravation of cancer prognosis and emergence of drug resistance in various cancers. Here, we targeted mutated and oncogenes harboring single-nucleotide missense mutations (T790M and R273H) that are associated with gefitinib resistance. Co-delivery of adenine base editor (ABE) and and SNP specific single-guide RNA via adenovirus (Ad) resulted in precise correction of the oncogenic mutations with high accuracy and efficiency and . Importantly, compared with a control group treated only with gefitinib, an EGFR inhibitor, co-treatment with Ad/ABE targeting SNPs in and in combination with gefitinib increased drug sensitivity and suppressed abnormal tumor growth more efficiently. Taken together, these results indicate that ABE-mediated correction of dual oncogenic SNPs can be an effective strategy for the treatment of drug-resistant cancers.

中文翻译：

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CRISPR介导的TP53和EGFR突变消除增强吉非替尼对肺癌的敏感性和抗肿瘤功效


多种致病性单核苷酸多态性（SNP）已被确定为导致癌症预后恶化和各种癌症出现耐药性的因素。在这里，我们针对含有与吉非替尼耐药相关的单核苷酸错义突变（T790M 和 R273H）的突变基因和癌基因。通过腺病毒 (Ad) 共同传递腺嘌呤碱基编辑器 (ABE) 和 SNP 特异性单向导 RNA，可以高精度、高效地精确校正致癌突变。重要的是，与仅用 EGFR 抑制剂吉非替尼治疗的对照组相比，与吉非替尼联合靶向 SNP 的 Ad/ABE 联合治疗可提高药物敏感性并更有效地抑制异常肿瘤生长。总而言之，这些结果表明 ABE 介导的双致癌 SNP 校正可能是治疗耐药癌症的有效策略。