Project 1: Race-related RNA splicing in non-small cell lung cancer: functional interrogation and therapeutic targeting

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ABSTRACT – Project 1 Lung and bronchus cancer is the leading cause of cancer-related deaths in the United States and in our institution’s state of North Carolina, with blacks having the highest number of deaths and being diagnosed three years younger on average than whites. Biological drivers of non-small cell lung cancer (NSCLC) in black patients remain underexplored, with only a small number of studies on race-related differences in actionable mutations and aggregate gene expression. As a result, these efforts have likely missed other important drivers of race- related NSCLC biological and clinical heterogeneity. The proposed work addresses the urgent need to functionally characterize and therapeutically target novel race-related RNA splicing targets in NSCLC. We are the first team to identify alternative RNA splicing differences in NSCLC between patients of African and European ancestry. Specifically, in lung squamous cell carcinomas (LUSCs), the number of race-related differentially spliced genes (DSGs) (4,830) far exceeded the number of genes exhibiting race-related differential aggregate gene expression (DEGs) (267) in the same tissues. Among the DSGs, 17% are reported to be oncogenes, tumor suppressor genes and/or drivers and 355 RNA splicing events within DSGs are associated with LUSC survival. Among the DEGs, 6% are reported to be cancer-related and 18 are associated with LUSC survival. A number of the DSGs and DEGs involve therapeutically targetable signaling pathways. Furthermore, we have mined The Cancer Genome Atlas (TCGA) and have identified DSGs and DEGs in additional LUSCs or lung adenocarcinomas (LUADs). The objectives of the proposed work are to extend this novel area of inquiry with significance for precision oncology in NSCLC disparities by 1) examining DSGs and DEGs in an expanded cohort of clinically relevant NSCLC subgroups of patients annotated for survival and smoking status, 2) functionally characterizing prioritized race-related alternative RNA splicing events, and 3) drugging prioritized race-related alternative RNA splicing events for therapeutic application. To reach these objectives, we propose to conduct three aims. Aim 1: To assess the expression of RNA splice variants and genes encoding trans-acting splicing factors across clinically relevant NSCLC subgroups in patients of African and European ancestry. Aim 2: To interrogate the functional significance of prioritized race-related RNA splice variants for the biology of NSCLC. Aim 3: A) To develop novel splice-switching oligonucleotide (SSO) morpholino drugs to modulate RNA splicing events critical to race-related NSCLC for therapeutic application and B) To identify available targeted therapeutic agents that inhibit race-related NSCLC based on dysregulated RNA splicing pathway(s). The rationale for and impact of this study is that it will 1) increase understanding of the molecular mechanisms underlying lung cancer disparities, 2) provide an abundance of novel RNA splicing-related targets for development of new biomarkers and therapeutic agents for NSCLC in patients of African ancestry, 3) when combined with TCGA data, this study will more than double the number of molecularly characterized NSCLC biospecimens from patients of African ancestry, and generate additional preclinical models, making such data and models available to the nationwide cohort of scientists conducting research on lung cancer and lung cancer disparities, and 4) position lead novel RNA splicing-targeted drugs for NSCLC in patients of African ancestry for in vivo studies. Ultimately, such precision oncology interventions and further studies enabled by the molecularly characterized cohort of biospecimens and models will have the potential to mitigate NSCLC disparities.