| Popis: |
BackgroundSCLC is a heterogeneous disease, consisting of intra-tumoral and inter-tumoral neuroendocrine (ASCL1/NEUROD1), mesenchymal-like, and YAP-driven transcriptional states. Lysine-specific demethylase 1 (LSD1/KDM1A) inhibitors have recently been progressed to clinical trials in small cell lung cancer (SCLC) based on a promising pre-clinical anti-tumor activity. Potential clinical limitation of LSD1 inhibitors are the heterogeneous drug responses that have been observed in SCLC cell lines and patient-derived models. Based on these observations, we studied molecular and transcriptional signatures that predict patient response to this class of drugs. MethodsLSD1 inhibitors, GSK690 and OG-86, were screened in a panel of SCLC cell line models facilitating the computational analysis of differentially expressed gene signatures correlated with intrinsic drug resistance, which were further evaluated experimentally in a SCLC mesenchymal variant form of NCI-H69 cells, NCI-H69V. Adaptive drug resistance was elucidated through bulk RNA-seq, ATAC-seq and single-cell RNA-seq, allowing study of transcriptional reprogramming in response to the drug treatment.ResultsEmploying SCLC patient-derived transcriptional signatures, we define that SCLC cell lines sensitive to LSD1 inhibitors are enriched in neuroendocrine transcriptional markers while cell lines enriched in a mesenchymal-like transcriptional program demonstrate intrinsic resistance to LSD1 inhibitors. We have identified a reversible, adaptive resistance mechanism to LSD1 inhibitors through epigenetic reprogramming to a TEAD4-driven mesenchymal-like state. ConclusionsOur data suggests that only a segment of SCLC patients, with a defined neuroendocrine differentiation state, will likely benefit from LSD1 inhibitors. It provides novel evidence for the selection of a TEAD4-driven mesenchymal-like subpopulation resistant to LSD1 inhibitors in SCLC patients that may require effective drug combinations to sustain effective clinical responses. |
