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Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q.
Neggers, Jasper E; Paolella, Brenton R; Asfaw, Adhana; Rothberg, Michael V; Skipper, Thomas A; Yang, Annan; Kalekar, Radha L; Krill-Burger, John M; Dharia, Neekesh V; Kugener, Guillaume; Kalfon, Jérémie; Yuan, Chen; Dumont, Nancy; Gonzalez, Alfredo; Abdusamad, Mai; Li, Yvonne Y; Spurr, Liam F; Wu, Westley W; Durbin, Adam D; Wolpin, Brian M; Piccioni, Federica; Root, David E; Boehm, Jesse S; Cherniack, Andrew D; Tsherniak, Aviad; Hong, Andrew L; Hahn, William C; Stegmaier, Kimberly; Golub, Todd R; Vazquez, Francisca; Aguirre, Andrew J.
Afiliación
  • Neggers JE; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Paolella BR; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Asfaw A; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Rothberg MV; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Skipper TA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Yang A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Kalekar RL; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Krill-Burger JM; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Dharia NV; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Kugener G; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kalfon J; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Yuan C; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Dumont N; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Gonzalez A; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Abdusamad M; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Li YY; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Spurr LF; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Wu WW; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Durbin AD; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Wolpin BM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Piccioni F; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Root DE; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Boehm JS; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Cherniack AD; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Tsherniak A; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Hong AL; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Hahn WC; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Stegmaier K; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Cancer and Blood Disorders Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Golub TR; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Vazquez F; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: vazquez@broadinstitute.org.
  • Aguirre AJ; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: andrew_aguirre@dfci.harvard.edu.
Cell Rep ; 33(11): 108493, 2020 12 15.
Article en En | MEDLINE | ID: mdl-33326793
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ATPasas de Translocación de Protón Vacuolares / Complejos de Clasificación Endosomal Requeridos para el Transporte / ATPasas Asociadas con Actividades Celulares Diversas / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ATPasas de Translocación de Protón Vacuolares / Complejos de Clasificación Endosomal Requeridos para el Transporte / ATPasas Asociadas con Actividades Celulares Diversas / Neoplasias Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos