Abstract PO-011: Synthetic lethal interaction between the ESCRT paralog enzymes VPS4A and VPS4B in SMAD4 or CDH1-deleted cancers (2020)

Abstract Somatic copy number alterations that result in loss of tumor suppressor gene function are important drivers of tumorigenesis. However, few existing therapeutic options to target oncogenic processes evoked by tumor suppressor gene inactivation exist. The discovery of synthetic lethal interactions with genetic drivers of cancer may yield new therapeutic strategies with cancer selective potential. We examined genome-scale CRISPR-SpCas9 and RNA interference screens to uncover new synthetic lethal vulnerabilities associated with the loss of common tumor suppressor genes (TSGs). The ATPases Vacuolar protein sorting 4 homolog A (VPS4A) and B (VPS4B) scored as strong synthetic lethal dependencies, with VPS4A selectively essential in cancers harboring loss of VPS4B adjacent to SMAD4 and VPS4B required in tumors with co-deletion of VPS4A and CDH1 (encoding E-cadherin). VPS4B resides 12.3 Mb away from the SMAD4 TSG on chromosome 18q and is lost in approximately 33% of all cancers, suggesting broad clinical applicability. Moreover, VPS4B is commonly lost in pancreatic cancer due to the frequent loss of SMAD4, highlighting VPS4A represents a promising target for this deadly cancer. VPS4A and VPS4B function as AAA ATPases forming a multimeric protein complex within the endosomal sorting complex required for transport (ESCRT) pathway to regulate membrane remodeling in a range of cellular processes. VPS4A suppression in cells with VPS4B/SMAD4 loss led to accumulation of ESCRT-III filaments, cytokinesis defects, nuclear deformation and micronucleation, which ultimately resulted in G2/M cell cycle arrest and apoptosis. Furthermore, upon VPS4A suppression, we observed potent in vivo tumor regression, which led to extended survival, in mouse subcutaneous xenograft models utilizing a pancreatic or rhabdomyosarcoma cancer cell line harboring VPS4B loss. CRISPR-SpCas9 screening and integrative genomic analysis revealed other ESCRT members, regulators of abscission and interferon signaling as modifiers of VPS4A dependency. Using the most comprehensive available CRISPR-SpCas9 and RNA-interference screening datasets to date, we provide a compendium of synthetic lethal vulnerabilities with TSG loss and credential VPS4A as a new and promising therapeutic target in cancers with VPS4B/SMAD4 deletion. Citation Format: Jasper E. Neggers, Brenton R. Paolella, Adhana Asfaw, Michael V. Rothberg, Thomas A. Skipper, Radha L. Kalekar, Michael J. Krill-Burger, Neekesh V. Dharia, Guillaume Kugener, Adam D. Durbin, Annan Yang, Nancy Dumont, Yvonne Y. Li, 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. Synthetic lethal interaction between the ESCRT paralog enzymes VPS4A and VPS4B in SMAD4 or CDH1-deleted cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-011.