Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
Cancer Res. 2023 May 2;83(9):1490-1502. doi: 10.1158/0008-5472.CAN-22-1549.
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 data sets 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.
Loss of the splicing factor RBM10 is mutually exclusive with p53 mutations, promotes tumorigenesis, and enhances the efficacy of spliceosome inhibition in EGFR-driven lung cancer.
在肺腺癌（LUAD）中，剪接因子 RBM10 的功能丧失性突变常与致癌性 EGFR 突变同时发生。深入了解 RBM10 缺失在 EGFR 突变 LUAD 中的功能后果和治疗影响，可能有助于确定更有效的治疗策略。在这里，对 LUAD 数据集的分析表明，RBM10 突变与肿瘤抑制基因 TP53 的突变是相互排斥的。在 EGFR 驱动的 LUAD 小鼠模型中，肺特异性敲除 Rbm10 或 Trp53 同样促进了肿瘤的发展，导致与癌症相关途径富集的重叠基因表达变化。RBM10 的缺失诱导了在小鼠和 LUAD 患者中一致的关键 RNA 剪接变化。重要的是，RBM10 缺陷赋予了 EGFR 突变 LUAD 细胞对剪接体抑制的高敏感性。与 EGFR 酪氨酸激酶抑制剂奥希替尼联合治疗，克服了耐药性，特别是在 RBM10 缺失的 LUAD 中。总之，这项研究确立了 RBM10 作为类似于 p53 的肿瘤抑制因子，并提供了针对 EGFR 驱动的 LUAD 中剪接机制的治疗策略。
剪接因子 RBM10 的缺失与 p53 突变相互排斥，促进肿瘤发生，并增强 EGFR 驱动的肺癌中剪接体抑制的疗效。
