Abstract A40: Specific mutations in the D1-D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors

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Abstract Valosin-containing protein (VCP) has been shown to be involved in various protein quality control pathways including ubiquitin proteasome system, endoplasmic reticulum-associated degradation, chromatin-associated degradation, protein aggregate processing, and autophagy. Recent studies also identified VCP as a lineage-specific essential gene in ovarian cancer. An orally bioavailable VCP inhibitor, CB-5083, is currently in phase I clinical trials because it shows therapeutic effects in multiple tumor xenograft models. However, the mechanism of resistance to CB-5083 is unknown. Here, we characterized molecular mechanism of resistance to CB-5083. Using incremental exposure to CB-5083, we established CB-5083-resistant ovarian cancer cells that showed 5-6 fold resistance in vitro compared to parental cells. Genomic and complementary DNA sequencing of the VCP coding region reveal a pattern of coselected mutations: (1) missense mutations at codon 470 in one copy resulting in increased ATPase activity and (2) nonsense or frameshift mutations at codon 606 or codon 616 in another copy causing the loss of allele-specific expression. Unbiased molecular docking studies show codon 470 as a putative binding site for CB-5083. Analysis of somatic mutations in cancer genomes from The Cancer Genome Atlas indicates that codon 616 contains hotspot mutations in VCP. Thus, identification of these mutations associated with in vitro resistance to VCP inhibitors may be useful as potential theranostic markers while screening for patients to enroll in clinical trials. VCP has emerged as a viable therapeutic target for several cancer types, and therefore targeting such hyperactive VCP mutants should aid in improving the therapeutic outcome in cancer patients. Citation Format: Prabhakar Bastola, Bret Freudenthal, Matthew Schaich, Tsui-Fen Chou, Taiping Gan, Feng Wang, Jeremy Chien. Specific mutations in the D1-D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A40.