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

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

Cell Rep. 2020 Dec 15;33(11):108493. doi: 10.1016/j.celrep.2020.108493.

Authors

Jasper E Neggers¹, Brenton R Paolella¹, Adhana Asfaw², Michael V Rothberg², Thomas A Skipper², Annan Yang³, Radha L Kalekar¹, John M Krill-Burger², Neekesh V Dharia⁴, Guillaume Kugener², Jérémie Kalfon², Chen Yuan³, Nancy Dumont², Alfredo Gonzalez², Mai Abdusamad², Yvonne Y Li¹, Liam F Spurr¹, Westley W Wu¹, Adam D Durbin⁴, Brian M Wolpin³, Federica Piccioni⁵, David E Root⁵, Jesse S Boehm², Andrew D Cherniack¹, Aviad Tsherniak², Andrew L Hong⁴, William C Hahn¹, Kimberly Stegmaier⁴, Todd R Golub⁶, Francisca Vazquez⁷, Andrew J Aguirre⁸

Affiliations

¹ 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.
² Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁴ 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.
⁵ Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ 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.
⁷ 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.
⁸ 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.

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.

Keywords: 16q loss; 18q loss; ESCRT; VPS4A; VPS4B; cancer; drug target; functional genomics; synthetic lethality; target identification.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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*

Substances

Endosomal Sorting Complexes Required for Transport
Vacuolar Proton-Translocating ATPases
ATPases Associated with Diverse Cellular Activities
VPS4A protein, human
VPS4B protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding