Cell Reports (Dec 2020)
Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q
- Jasper E. Neggers,
- Brenton R. Paolella,
- Adhana Asfaw,
- Michael V. Rothberg,
- Thomas A. Skipper,
- Annan Yang,
- Radha L. Kalekar,
- John M. Krill-Burger,
- Neekesh V. Dharia,
- Guillaume Kugener,
- Jérémie Kalfon,
- Chen Yuan,
- Nancy Dumont,
- Alfredo Gonzalez,
- Mai Abdusamad,
- Yvonne Y. Li,
- Liam F. Spurr,
- Westley W. Wu,
- Adam D. Durbin,
- Brian M. Wolpin,
- Federica Piccioni,
- David E. Root,
- Jesse S. Boehm,
- Andrew D. Cherniack,
- Aviad Tsherniak,
- Andrew L. Hong,
- William C. Hahn,
- Kimberly Stegmaier,
- Todd R. Golub,
- Francisca Vazquez,
- Andrew J. Aguirre
Affiliations
- Jasper E. Neggers
- 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
- Brenton R. Paolella
- 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
- Adhana Asfaw
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Michael V. Rothberg
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Thomas A. Skipper
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Annan Yang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Radha L. Kalekar
- 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
- John M. Krill-Burger
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Neekesh V. Dharia
- 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
- Guillaume Kugener
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Jérémie Kalfon
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Nancy Dumont
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Alfredo Gonzalez
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Mai Abdusamad
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Yvonne Y. Li
- 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
- Liam F. Spurr
- 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
- Westley W. Wu
- 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
- Adam D. Durbin
- 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
- Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Federica Piccioni
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- David E. Root
- Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Jesse S. Boehm
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Andrew D. Cherniack
- 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
- Aviad Tsherniak
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Andrew L. Hong
- 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
- William C. Hahn
- 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
- Kimberly Stegmaier
- 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
- Todd R. Golub
- 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
- Francisca Vazquez
- 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; Corresponding author
- Andrew J. Aguirre
- 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; Corresponding author
- Journal volume & issue
-
Vol. 33,
no. 11
p. 108493
Abstract
Summary: 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.
