Abstract C087: Drugging UBXN2A, a tumor suppressor protein in colorectal cancer: Selective suppression of mTORC2-AKT pathway in patient-derived xenograft cells

Abstract Colorectal cancer (CRC) causes approximately 900,000 deaths annually worldwide. Despite considerable advances to improve CRC survival over the last decade, therapeutic challenges remain due to rapid metastatic dissemination of primary tumors as well as the inability to safely and effectively target these tumors. Therefore, understanding the mechanisms underlying the multistep metastatic programs activated in CRC tumors is critical for developing novel therapies to improve the management of this advanced disease. We have previously shown that veratridine (VTD), a lipid-soluble alkaloid extracted from Liliaceae plants, can transcriptionally increase UBXN2A, a potent tumor suppressor protein in CRC. UBXN2A induces 26S proteasomal degradation of the Rictor protein, a key member in the mTORC2 tumorigenic signaling pathway. Destabilization of Rictor protein by VTD decreases Akt phosphorylation at Ser473, which is responsible for metastatic signaling downstream of the mTORC2 pathway. We hypothesized that the VTD-UBXN2A axis inhibits the overactive Rictor-mTORC2 pathway in CRC, resulting in the suppression of mTORC2’s downstream pathways, including tumor cell migration and invasion. Using a set of patient-derived xenograft (PDX) cell lines from both early- and late-onset CRC, we determined VTD’s biological and therapeutic effects as these cells have the original genetic profile of the human tumors from which they were derived. Western Blot (WB), flow-cytometry analysis (FACS), and confocal microscopy revealed that VTD can effectively target the mTORC2-Akt pathways in PDX cells in a UBXN2A-dependent manner. Completing this project will provide new insights into the functions of UBXN2A, a ubiquitin-like protein, in inhibiting tumor metastasis and support the notion that VTD is an attractive and promising treatment strategy for metastatic CRC. Citation Format: Morgan Montgomery1, Morgan Eikanger1, Khosrow Rezvani1. Drugging UBXN2A, a tumor suppressor protein in colorectal cancer: Selective suppression of mTORC2-AKT pathway in patient-derived xenograft cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C087.