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. 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