Abstract LB-053: VPS4A is a synthetic lethal target in VPS4B-deficient cancers due to co-deletion with SMAD4

Abstract

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). Vacuolar protein sorting 4 homolog A (VPS4A) scored as a strong, selective dependency in cancer cells with genomic loss of the SMAD4 tumor suppressor due to co-deletion of VPS4A's paralog gene, VPS4B. 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. 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 observerd potent in vivo tumor regression, which led to extended survival, in mouse subcutaneous xenograft models with human cancer cell lines harboring VPS4B loss. Finally, genome-scale CRISPR-SpCas9 loss-of-function screening revealed other ESCRT pathway members and regulators of cellular abscission 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, John M. Krill-Burger, Andrew L. Hong, Guillaume Kugener, Jeremie Kalfon, Annan Yang, Chen Yuan, Nancy Dumont, Alfredo Gonzalez, Mai Abdusamad, Yvonne Y. Li, Liam F. Spurr, Westley W. Wu, Federica Piccioni, Brian M. Wolpin, David E. Root, Jesse S. Boehm, Andrew D. Cherniack, Aviad Tsherniak, Todd R. Golub, Francisca Vazquez, Andrew J. Aguirre. VPS4A is a synthetic lethal target in VPS4B-deficient cancers due to co-deletion with SMAD4 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-053.