Often referred to as a recalcitrant cancer, small cell lung cancer (SCLC) is a the most aggressive form of lung cancer, with an overall five-year survival rate of 6%. Although tumours initially respond well to platinum-based chemotherapy, resistance rapidly develops. A challenging aspect of this chemoresistance lies in the co-existence of multiple transcriptional subtypes within an individual SCLC tumour. Namely, the YAP1-high SCLC (SCLC-Y) subtype, a non-neuroendocrine variant of SCLC, is thought to be more chemoresistant relative to classical neuroendocrine SCLC subtypes. Thus, understanding the therapeutic vulnerabilities underpinning SCLC-Y tumourigenesis is paramount to overcoming chemoresistance.
In order to investigate these therapeutic vulnerabilities, we hypothesised that there are subtype-specific mutations associated with SCLC-Y given the high tumour mutational burden in SCLC. Analysis of the genomic landscape of human SCLC cell lines (n=50) revealed 26 frequently (≥ 50% occurrence) mutated genes unique to SCLC-Y. Of these 26 frequently mutated genes, a mutation in a component of the SWI/SNF chromatin remodelling complex was identified in 5 of 8 SCLC-Y cell lines. Moreover, this SWI/SNF-associated mutation was mutually exclusive to RB1 mutation within the SCLC-Y subtype, suggesting an alternative mechanism driving tumorigenesis in SCLC-Y.
To further evaluate the functional significance of this SWI/SNF mutation in SCLC-Y, we employed immunohistochemical staining on subcutaneous tumours generated from a human SCLC-Y cell line (SW1271). Our results confirm that the SCLC-Y tumour was deficient in this component of the SWI/SNF chromatin remodelling complex, albeit proficient in RB1. Interestingly, this immunohistochemical staining pattern was not observed with other SCLC subtypes (NCI-H69, NCI-H82 and NCI-H526). Future investigations of this SWI/SNF mutation in our cohort of patient-derived xenograft models that exhibit YAP1 expression will reveal the functional significance of the SWI/SNF complex in SCLC-Y tumorigenesis.