EIF6 conditions drug-tolerant persister-like transdifferentiation in small cell lung carcinoma (eIF6_KD)

Drug-tolerant persister cells withstand treatments by adapting their identity through lineage-dependent plasticity during systemic anti-cancer therapies. This phenomenon is evident in small-cell lung carcinoma (SCLC), a lethal neuroendocrine cancer initially responsive (60-80%) to platinum-based chemotherapy but succumbing to resistance within 6 months in advanced stages. This resistance associates with the transdifferentiation of residual tumour cells into a non-neuroendocrine state, a process intricately tied to SCLC's chemotolerance, yet molecular mechanisms governing this lineage conversion remain completed understood. Here we use paired cytoplasmic RNA-seq and polysomal RNA-seq to compare gene expression between NE and non-NE SCLC cell lines on both transcriptional and translational level. We report that first-line chemotherapy induces translation initiation factor eIF6 in drug-tolerant persister-like cells in SCLC, correlating with the non-neuroendocrine state in SCLC. Intervening eIF6 inhibits non-neuroendocrine transdifferentiation, thus enhancing SCLC responsiveness to chemotherapy. This study sheds light on eIF6's potential therapeutic interventions to mitigate treatment resistance in SCLC. Overall design: To investigate function of eIF6 in H69 and H69M cells, we established stable eIF6-KD H69 and H69M cell lines by lenitivirus infection containing shRNA targeting eIF6. Comparative gene expression profiling analysis of RNA-seq data for H69_sheIF6 cells vs. H69_shNTC cells and H69M_sheIF6 cells vs. H69M_shNTC cells