A novel pipeline for prioritizing cancer type‐specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas

There is limited guidance on exploiting the genome‐wide loss‐of‐function CRISPR screens in cancer Dependency Map (DepMap) to identify new targets for individual cancer types. This study integrated multiple tools to filter these data in order to seek new therapeutic targets specific to head and neck squamous cell carcinoma (HNSCC). The resulting pipeline prioritized 143 targetable dependencies that represented both well‐studied targets and emerging target classes like mitochondrial carriers and RNA‐binding proteins. In total, 14 targets had clinical inhibitors used for other cancers or nonmalignant diseases that hold near‐term potential to repurpose for HNSCC therapy. Comparing inhibitor response data that were publicly available for 13 prioritized targets between the cell lines with high vs. low dependency on each target uncovered novel therapeutic potential for the PAK2 serine/threonine kinase. PAK2 gene dependency was found to be associated with wild‐type p53, low PAK2 mRNA, and diploid status of the 3q amplicon containing PAK2. These findings establish a generalizable pipeline to prioritize clinically relevant targets for individual cancer types using DepMap. Its application to HNSCC highlights novel relevance for PAK2 inhibition and identifies biomarkers of PAK2 inhibitor response.