Genomic and transcriptomic characterization of relapsed small cell lung cancer through rapid research autopsy

Abstract Introduction Relapsed small cell lung cancer (SCLC) is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive due to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies. Methods We performed whole exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five relapsed SCLC patients. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single sample gene set enrichment analyses on tumor/normal transcriptome data from autopsy and additional primary and relapsed SCLC datasets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (ASCL1, NEUROD1) and non-neuroendocrine (YAP1, POU2F3) SCLC subtypes. Results Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further showed a non-inflamed phenotype in neuroendocrine SCLC subtypes (ASCL1, NEUROD1) associated with decreased expression of genes involved in adaptive anti-tumor immunity, while non-neuroendocrine subtypes (YAP1, POU2F3) demonstrated a more inflamed phenotype. Conclusion Our results demonstrate substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, they show that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that mechanisms of innate and acquired therapeutic resistance are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.