Deubiquitinase Vulnerabilities Identified through Activity-BasedProtein Profiling in Non-Small Cell Lung Cancer br

To aid in the prioritization of deubiquitinases(DUBs) as anticancer targets, we developed an approachcombining activity-based protein profiling (ABPP) with massspectrometry in both non-small cell lung cancer (NSCLC) tumortissues and cell lines along with analysis of available RNAinterference and CRISPR screens. We identified 67 DUBs inNSCLC tissues, 17 of which were overexpressed in adenocarcino-ma or squamous cell histologies and 12 of which scored as affectinglung cancer cell viability in RNAi or CRISPR screens. We used theCSN5 inhibitor, which targets COPS5/CSN5, as a tool tounderstand the biological significance of one of these 12 DUBs,COPS6, in lung cancer. Our study provides a powerful resource to interrogate the role of DUB signaling biology and nominatesdruggable targets for the treatment of lung cancer subtypes.