SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing [RNA-seq]
Small Cell Lung Cancer (SCLC) can be classified into transcriptional subtypes with distinct degrees of neuroendocrine (NE) differentiation. Recent evidence supports plasticity among subtypes with a bias toward adoption of low-NE states during disease progression or upon acquired chemotherapy resistance. Here, we identify a role for SMARCA4, the catalytic subunit of the SWI/SNF complex, as a regulator of subtype shift in SCLC. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, suppressing NE programs. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST splicing. The SMARCA2/4 inhibitor FHD-286 induces loss of NE features and drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC. Overall design: To study the role of SMARCA4/2 in regulating the neuroendocrine phenotype in SCLC, we pharmacologically inhibited  this target using FHD-286 and performed gene expression profiling analysis by RNAseq. We treated H146 and H82 cells for 14 days with 100nM of FHD-286. Comparative gene expression profiling of RNAseq data for H82 and H146 treated vs untreated cells.