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. Studies suggest that SWI/SNF complexes bind to the DNA-histone scaffold and initiate transcription via the recruitment of vital cellular transcriptional machinery including histone acetyltransferases. Importantly, 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 overall 5-year survival of 16%. Mutations in SMARCA4, a core member of the SWI/SNF complexes, are believed to occur in 6% of LAC. Using a panel of SMARCA4 wildtype and mutant human LAC cell lines we show a marked sensitivity of the HDACi, Panobinostat, to SMARCA4-null cell lines. Furthermore, sustained low-dose treatment of the SMARCA4-null LAC cell line, A549, results in gene expression changes consistent with differentiation, including the down regulation of lung progenitor markers and increased expression of type II epithelial cell markers. Lastly, Panobinostat treatment significantly reduces tumour volume, extends survival and drives cell differentiation in an A549 xenograft model. Together, these data suggest that low-dose Panobinostat promotes differentiation of SMARCA4-null LAC.