論文 - 詳細
| RRC ID | 63224 |
|---|---|
| 著者 | Neggers 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. |
| タイトル | Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q. |
| ジャーナル | Cell Rep |
| 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. |
| 巻・号 | 33(11) |
| ページ | 108493 |
| 公開日 | 2020-12-15 |
| DOI | 10.1016/j.celrep.2020.108493 |
| PII | S2211-1247(20)31482-0 |
| PMID | 33326793 |
| PMC | PMC8374858 |
| MeSH | ATPases Associated with Diverse Cellular Activities / metabolism* Cell Line, Tumor Endosomal Sorting Complexes Required for Transport / metabolism* Humans Neoplasms / genetics* Vacuolar Proton-Translocating ATPases / metabolism* |
| IF | 8.109 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 31 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | GSU(RCB2278) JHOS-2(RCB1521) KP4(RCB1005) OVK18(RCB1903) |