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Cell Rep DOI:10.1016/j.celrep.2020.108493

Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q.

Publication TypeJournal Article
Year of Publication2020
AuthorsNeggers, JE, Paolella, BR, Asfaw, A, Rothberg, MV, Skipper, TA, Yang, A, Kalekar, RL, Krill-Burger, JM, Dharia, NV, Kugener, G, Kalfon, J, Yuan, C, Dumont, N, Gonzalez, A, Abdusamad, M, Li, YY, Spurr, LF, Wu, WW, Durbin, AD, Wolpin, BM, Piccioni, F, Root, DE, Boehm, JS, Cherniack, AD, Tsherniak, A, Hong, AL, Hahn, WC, Stegmaier, K, Golub, TR, Vazquez, F, Aguirre, AJ
JournalCell Rep
Volume33
Issue11
Pages108493
Date Published2020 12 15
ISSN2211-1247
Abstract

Few therapies target the loss of tumor suppressor genes in cancer. We examine CRISPR-SpCas9 and RNA-interference loss-of-function screens to identify new therapeutic targets associated with genomic loss of tumor suppressor genes. The endosomal sorting complexes required for transport (ESCRT) ATPases VPS4A and VPS4B score as strong synthetic lethal dependencies. VPS4A is essential in cancers harboring loss of VPS4B adjacent to SMAD4 on chromosome 18q and VPS4B is required in tumors with co-deletion of VPS4A and CDH1 (E-cadherin) on chromosome 16q. We demonstrate that more than 30% of cancers selectively require VPS4A or VPS4B. VPS4A suppression in VPS4B-deficient cells selectively leads to ESCRT-III filament accumulation, cytokinesis defects, nuclear deformation, G2/M arrest, apoptosis, and potent tumor regression. CRISPR-SpCas9 screening and integrative genomic analysis reveal other ESCRT members, regulators of abscission, and interferon signaling as modifiers of VPS4A dependency. We describe a compendium of synthetic lethal vulnerabilities and nominate VPS4A and VPS4B as high-priority therapeutic targets for cancers with 18q or 16q loss.

DOI10.1016/j.celrep.2020.108493
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33326793?dopt=Abstract

Alternate JournalCell Rep
PubMed ID33326793
PubMed Central IDPMC8374858
Grant ListU01 CA224146 / CA / NCI NIH HHS / United States
K08 CA218420 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States