Open AccessSynthetic lethality between VPS 4A and VPS 4B triggers an inflammatory response in colorectal cancer
Author(s) -
Szymańska Ewelina,
Nowak Paulina,
Kolmus Krzysztof,
Cybulska Magdalena,
Goryca Krzysztof,
DerezińskaWołek Edyta,
SzumeraCiećkiewicz Anna,
BrewińskaOlchowik Marta,
Grochowska Aleksandra,
Piwocka Katarzyna,
ProchorecSobieszek Monika,
Mikula Michał,
Miączyńska Marta
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910812
Subject(s) - colorectal cancer , cancer , medicine
Abstract Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS 4B gene, encoding an ATP ase involved in ESCRT ‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer ( CRC ). We observed downregulation of VPS 4B mRNA and protein levels from CRC patient samples. We identified VPS 4A paralog as a synthetic lethal interactor for VPS 4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS 4 inhibitors for precision therapy of VPS 4B‐deficient cancers.