SMARCB1 Maintains Lineage Fidelity in Clear Cell Renal Cell Carcinoma

Abstract

Lineage-specific transcription factors have emerged as a promising class of essential genes in cancer. The best examples of leveraging this phenomenon in the clinic is targeting the androgen receptor and the oestrogen receptor in prostate and breast cancer respectively. Despite the success of these therapies, the mechanisms that maintain lineage fidelity in advanced cancer clones, and whether lineage factor pathways could be exploited in other cancer types remain poorly understood. Using clear cell renal cell carcinoma (ccRCC) as a model, I characterise mechanisms that underlie lineage factor dependence in cancer. Using CRISPR/Cas9 loss-of-function screening coupled with in vitro and in vivo validation I show that the loss of SMARCB1, a member of the SWI/SNF chromatin remodelling complex, confers an advantage to ccRCC cells upon inhibition of the essential renal lineage factor PAX8. SMARCB1 knockout (KO) leads to large-scale loss of a kidney-specific enhancer program, conversion to a cellular state resembling that of rhabdoid tumours, and the re-activation of proliferative pathways. Using a second CRISPR/Cas9 screen, I show that these proliferative pathways are underpinned by the acquisition of new transcriptional dependencies. These dependencies represent rare essential genes across different lineage-specific and oncogenic pathways, a principle validated in a large-scale CRISPR/Cas9 screening data set comprising hundreds of cancer cell lines. In summary, dependence on tissue-specific lineage factors in cancer can be modulated via epigenetic remodelling.