Data from <i>RBM10</i> Loss Promotes <i>EGFR</i>-Driven Lung Cancer and Confers Sensitivity to Spliceosome Inhibition

Abstract

<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>