Deubiquitinase Vulnerabilities Identified through Activity-Based Protein Profiling in Non-Small Cell Lung Cancer

To
aid in the prioritization of deubiquitinases (DUBs) as anticancer
targets, we developed an approach combining activity-based protein
profiling (ABPP) with mass spectrometry in both non-small cell lung
cancer (NSCLC) tumor tissues and cell lines along with analysis of
available RNA interference and CRISPR screens. We identified 67 DUBs
in NSCLC tissues, 17 of which were overexpressed in adenocarcinoma
or squamous cell histologies and 12 of which scored as affecting lung
cancer cell viability in RNAi or CRISPR screens. We used the CSN5
inhibitor, which targets COPS5/CSN5, as a tool to understand 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 nominates druggable targets for the treatment of lung
cancer subtypes.