Convergent and divergent determinants of heterogeneity, biomarkers, and plasticity in thoracic and prostate neuroendocrine tumors

BackgroundSmall cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine carcinoma and has a dismal prognosis with limited progress in treatment options. SCLC tumors are characterized by by transcription factor (TF) expression: ASCL1, NEUROD1, POU2F3, or YAP1. Histological transformation from lung adenocarcinoma (LUAD) to transformed small-cell carcinoma (T-SCLC) is a signature example of lineage plasticity (LP) and mechanism of acquired resistance in upto 15% of EGFR-mutant LUADs. Patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR) and develop AR-indifferent neuroendocrine prostate cancer (NEPC). Like SCLC, NEPC tumors also show a frequent loss of RB1 and TP53 and expression of ASCL1 and NEUROD1.MethodsWe performed an analysis of multi-omic sequencing of the clinical samples from LUAD, SCLC (de novo and transformed), and NEPC.ResultsWe observed upregulation of neuroendocrine markers (SYP, SYN1, INSM1), Notch inhibition (DLL3, HES6), neural differentiation (SEZ6), and chromatin remodeling (PRC2 complex genes) in post-T SCLC. We show the downregulation of genes involved in immune response, including neutrophil degranulation, cytokine signaling, T-cell immunity, and complement system function. Analyses of differential methylation of transcription factor (TF) binding motifs revealed hypomethylation of binding motifs of key master regulators of neuroendocrine differentiation in the post-T samples, including ASCL1 and NEUROD1 and demethylation of binding motifs for TFs involved in WNT signaling and stemness in the post-T SCLC samples. We observed pathways of convergence between SCLC and NEPC in heterogeneity, plasticity, and therapeutic vulnerabilities. Finally, inhibition of epigenetic modifier, EZH2, and PI3K/AKT inhibitors re-sensitized the EGFR mutant LUAD PDXs to osimertinib and significantly delayed transformation, highlighting their role as potential therapeutic targets.ConclusionsWe highlight key transcriptional, epigenetic regulators and immune microenvironmental changes during LP in lung cancer, highlighting therapeutic approaches that may inform treatment decisions in T-SCLC and NEPC.FundingHas not received any funding.DisclosureThe author has declared no conflicts of interest.