在肺腺癌（LUAD）中，剪接因子RBM10的功能丧失突变频繁与致癌EGFR突变共同存在。对于EGFR突变的LUAD中RBM10损失的功能后果和治疗影响的详细理解，可以帮助识别更有效的治疗策略。本研究分析了LUAD数据集，发现RBM10突变与肿瘤抑制因子基因TP53的突变互相排斥。在EGFR驱动的LUAD小鼠模型中，肺特异性消融Rbm10或Trp53同样促进了肿瘤的发展，导致在癌症相关通路中富集的重叠基因表达变化。RBM10丧失诱导了小鼠和LUAD患者中一致的关键RNA剪接变化。重要的是，RBM10缺陷导致了EGFR突变的LUAD细胞对剪接体抑制剂高敏感性。联合使用剪接体抑制剂改善了EGFR酪氨酸激酶抑制剂奥西替尼的治疗疗效，克服了药物抗性，特别是在RBM10缺陷的LUAD中。综上，本研究将RBM10确立为类似于p53的肿瘤抑制因子，并提供了一个针对EGFR驱动的LUAD中剪接机制的治疗策略。

In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic EGFR mutations. A detailed understanding of the functional consequences and therapeutic impact of RBM10 loss in EGFR-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD datasets indicated that RBM10 mutations are mutually exclusive with mutations in the tumor suppressor gene TP53. In an EGFR-driven LUAD mouse model, lung-specific ablation of either Rbm10 or Trp53 similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways. RBM10 loss induced key RNA splicing changes concordant in mice and LUAD patients. Importantly, RBM10 deficiency conferred high sensitivity to spliceosome inhibition in EGFR-mutated LUAD cells. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in RBM10-deficient LUAD. Together, this study establishes RBM10 as a tumor suppressor akin to p53 and provides a therapeutic strategy of targeting the splicing machinery in EGFR-driven LUAD.