Selective Regulation of Tuft Cell-Like Small Cell Lung Cancer by Novel Transcriptional Co-activators C11orf53 and COLCA2

Abstract The DepMap project has generated a huge resource for investigating selectively essential genes, which represent potential cancer therapeutic targets. However, manually sorting out which of the hundreds of selectively essential genes is understudied and warrants investigations is time-consuming and probably not practical. To efficiently identify uncharacterized, selectively essential genes, we collected and ranked the 347 selectively essential genes from the DepMap dataset by their PubMed publication counts, based on the assumption that genes with low publication counts are un-studied or under-studied. We successfully validated two of the top candidates in our ranking system, C11orf53 and COLCA2, as new vulnerabilities that are selectively essential in the class II POU domain transcription factor POU2F3-dependent tuft cell-like small cell lung cancer (SCLC) cell lines. Importantly, we found that the sequence motif, which mediates physical interactions of the transcriptional co-activator POU2AF1 with two of the class II POU domain-containing family of transcription factors (POU2F1 and POU2F2), is also present in the N-terminal regions of C11orf53 and COLCA2. We further confirmed that 1) COLCA2 physically interacts with POU2F3 through this conserved sequence motif; 2) this interaction is important for COLCA2 to regulate tuft cell-like SCLC cell growth, and 3) both C11orf53 and COLCA2 contain transcriptional co-activator domains. Consistently, we find similar transcriptomic changes in response to the loss of COLCA2 or POU2F3 in SCLC cells. In summary, our analysis pipeline enables identification and prioritization of understudied but important, selectively essential genes, leading to the identification of two new transcriptional co-activators for the class II POU domain transcription factors. Disruption of this important physical interaction is predicted to be a potential therapeutic strategy to selectively inhibit tuft cell-like SCLCs.