Synthetic Lethal Interaction Between The Escrt Paralog Enzymes Vps4a And Vps4b In Cancers With Chromosome 18q Or 16q Deletion

Somatic copy number alterations constitute distinctive driver events of tumorigenesis. Hence, the identification of pharmacologically tractable targets related to somatic copy number alterations represents an opportunity for drug discovery to achieve cancer-selective therapeutics. Here, we examined genome-scale CRISPR-SpCas9 and RNA-interference loss-of-function screens to identify new cancer therapeutic targets associated with genomic loss of common tumor suppressor genes. The ESCRT ATPases VPS4A and VPS4B scored as strong synthetic lethal dependencies, with VPS4A selectively essential in cancers harboring loss of VPS4B adjacent to SMAD4 on chromosome 18q and VPS4B required in tumors with co-deletion of VPS4A and CDH1 (encoding E-cadherin) on chromosome 16q.