Impaired differentiation is a common feature of cancer. In contrast to chemotherapy, the goal of differentiation therapy is to exhaust the malignant potential of tumour cells through the reactivation of developmental programs rather than cell death. The Switch/Sucrose Non-Fermentable (SWI/SNF) DNA remodelling complexes play a vital role in regulating cellular differentiation and have been strongly implicated in cancer. SWI/SNF complexes bind to the DNA-histone scaffold and initiate transcription via the recruitment of vital cellular transcriptional machinery including histone acetyltransferases. Next-generation sequencing has identified mutations in at least 10 genes encoding subunits of the SWI/SNF complexes that are recurrently mutated in cancers originating in nearly every body tissue, collectively occurring in >25% of all human malignancies. Lung adenocarcinoma (LAC) accounts for >40% of all lung cancers and has an 18% of overall 5-year survival. Mutations in SMARCA4 are believed to occur in >12% of LAC.
Using a panel of characterized human LAC cell lines we show a marked sensitivity of the HDACi, HDACi, exclusively to SMARCA4-null LAC only. This is preceded by increased H3K27ac, decreased H3K27me3 and decreased EZH2 expression. Sustained low-dose panobinostat treatment of SMARCA4-mutant LAC cell lines, results in unique gene expression changes consistent with differentiation, not observed in SMARCA4 wildtype lines. To further demonstrate the specific dependence of loss of SMARCA4 on response to HDACi, we generated three isogenic cell lines using CRISPR KO. H358, H441 and H2009 SMARCA4 KO LAC cell lines were markedly more sensitive to panobinostat than their wildtype parental lines. Lastly, panobinostat treatment results in tumour growth arrest and increased survival in SMARCA4-deficient LAC cell line xenografts and PDX models in vivo but not in SMARCA4-intact LAC models. Together, these data suggest that SMARCA4-deficient LAC are dependent on HDAC activity to maintain an undifferentiated state and are therefore highly susceptible to epigenetic differentiation therapy.