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 EGFR and TP53 oncogenes harboring single-nucleotide missense mutations (EGFR-T790M and TP53-R273H) that are associated with gefitinib resistance. Co-delivery of adenine base editor (ABE) and EGFR- and TP53-SNP specific single-guide RNA via adenovirus (Ad) resulted in precise correction of the oncogenic mutations with high accuracy and efficiency in vitro and in vivo. Importantly, compared with a control group treated only with gefitinib, an EGFR inhibitor, co-treatment with Ad/ABE targeting SNPs in TP53 and EGFR 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 突变消融增强了吉非替尼在肺癌中的敏感性和抗肿瘤疗效


多种致病性单核苷酸多态性 （SNP） 已被确定为各种癌症癌症预后恶化和出现耐药性的促成因素。在这里，我们靶向了携带与吉非替尼耐药相关的单核苷酸错义突变 （EGFR-T790M 和 TP53-R273H） 的突变 EGFR 和 TP53 癌基因。腺嘌呤碱基编辑器 （ABE） 以及 EGFR 和 TP53-SNP 特异性单向导 RNA 通过腺病毒 （Ad） 共同递送，可在体外和 体内以高准确度和高效 的方式精确纠正致癌突变。重要的是，与仅使用 EGFR 抑制剂吉非替尼治疗的对照组相比，与 Ad/ABE 联合治疗靶向 TP53 中的 SNP 和 EGFR 联合吉非替尼提高了药物敏感性并更有效地抑制了异常肿瘤生长。综上所述，这些结果表明，ABE 介导的双致癌 SNP 校正可以成为治疗耐药癌症的有效策略。