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

Abstract

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