SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing Journal Article
| Authors: | Redin, E.; Sridhar, H.; Zhan, Y. A.; Mello, B. P.; Zhong, H.; Durani, V.; Sabet, A.; Manoj, P.; Linkov, I.; Qiu, J.; Koche, R. P.; de Stanchina, E.; Astorkia, M.; Betel, D.; Quintanal-Villalonga, Á; Rudin, C. M. |
| Article Title: | SMARCA4 controls state plasticity in small cell lung cancer through regulation of neuroendocrine transcription factors and REST splicing |
| Abstract: | Introduction: 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. Methods: ATACseq and RNAseq experiments were performed in SCLC cells after pharmacological inhibition of SMARCA4. DNA binding of SMARCA4 was characterized by ChIPseq in high-NE SCLC patient derived xenografts (PDXs). Enrichment analyses were applied to transcriptomic data. Combination of FHD-286 and afatinib was tested in vitro and in a set of chemo-resistant SCLC PDXs in vivo. Results: SMARCA4 expression positively correlates with that of NE genes in both SCLC cell lines and patient tumors. Pharmacological inhibition of SMARCA4 with FHD-286 induces the loss of NE features and downregulates neuroendocrine and neuronal signaling pathways while activating non-NE factors. SMARCA4 binds to gene loci encoding NE-lineage transcription factors ASCL1 and NEUROD1 and alters chromatin accessibility, enhancing NE programs. Enrichment analysis applied to high-confidence SMARCA4 targets confirmed neuron related pathways as the top GO Biological processes regulated by SMARCA4 in SCLC. In parallel, SMARCA4 also controls REST, a known suppressor of the NE phenotype, by regulating SRRM4-dependent REST transcript splicing. Furthermore, SMARCA4 inhibition drives ERBB pathway activation in SCLC, rendering SCLC tumors sensitive to afatinib. Conclusions: This study nominates SMARCA4 as a key regulator of the NE state plasticity and defines a novel therapeutic strategy for SCLC. © The Author(s) 2024. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; genetics; cancer combination chemotherapy; nonhuman; mouse; animal; metabolism; animals; mice; animal tissue; nuclear protein; protein dna binding; lung neoplasms; animal experiment; animal model; gene locus; lung cancer; transcription factor; in vivo study; tumor xenograft; drug effect; pathology; cell line, tumor; transcriptomics; transcription factors; cancer resistance; nuclear proteins; lung tumor; gene expression regulation; gene expression regulation, neoplastic; epigenetics; tumor cell line; down regulation; drug therapy; drug determination; repressor protein; repressor proteins; genetic code; dna helicases; dna helicase; rna sequence; targeted therapies; small cell lung cancer; small cell lung carcinoma; plasticity; sclc; brg1 protein; afatinib; humans; human; female; article; smarca4 protein, human; camibirstat; re1 silencing transcription factor; re1-silencing transcription factor |
| Journal Title: | Journal of Hematology & Oncology |
| Volume: | 17 |
| ISSN: | 1756-8722 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2024-07-30 |
| Start Page: | 58 |
| Language: | English |
| DOI: | 10.1186/s13045-024-01572-3 |
| PUBMED: | 39080761 |
| PROVIDER: | scopus |
| PMCID: | PMC11290012 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Álvaro Quintanal‑Villalonga and Charles M. Rudin -- Erratum published at DOI: 10.1186/s13045-024-01609-7 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work