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.

<p>Supplementary Table S2</p>

<p>Supplementary Table S1</p>

<p>Supplementary Table S2</p>

<p>Supplementary Table S5</p>

<p>Supplementary Table S4</p>

<div>Abstract<p>In lung adenocarcinoma (LUAD), loss-of-function mutations in the splicing factor RBM10 frequently co-occur with oncogenic <i>EGFR</i> mutations. A detailed understanding of the functional consequences and therapeutic impact of <i>RBM10</i> loss in <i>EGFR</i>-mutant LUAD could help identify more effective treatment strategies. Here, analysis of LUAD data sets indicated that <i>RBM10</i> mutations are mutually exclusive with mutations in the tumor suppressor gene <i>TP53</i>. In an <i>EGFR</i>-driven LUAD mouse model, lung-specific ablation of either <i>Rbm10</i> or <i>Trp53</i> similarly promoted tumor development, leading to overlapping gene expression changes enriched in cancer-related pathways. <i>RBM10</i> loss induced key RNA splicing changes concordant in mice and LUAD patients. Importantly, <i>RBM10</i> deficiency conferred high sensitivity to spliceosome inhibition in <i>EGFR</i>-mutated LUAD cells. Combined treatment with spliceosome inhibitor improved the therapeutic efficacy of EGFR tyrosine kinase inhibitor osimertinib and overcame drug resistance, especially in <i>RBM10</i>-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 <i>EGFR</i>-driven LUAD.</p>Significance:<p>Loss of the splicing factor RBM10 is mutually exclusive with p53 mutations, promotes tumorigenesis, and enhances the efficacy of spliceosome inhibition in <i>EGFR</i>-driven lung cancer.</p></div>

<p>Supplementary Figs. S1-S6</p>