Abstract 3027: Killing two birds with one stone: veratridine functions as a dual inhibitor of both hyperactive mTORC2 and mitochondria in colon cancer cells

Abstract Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. There has been an increase in early-onset CRC (patients under age 50) incidences in all ethnicities. Early-onset CRC introduces another major health challenge as these patients are commonly diagnosed with advanced, metastatic forms of CRC, resulting in higher mortality rates, showing the clear need to develop safer and more effective therapies. There has been significant progress in understanding the tumorigenic pathways responsible for the invasion and metastasis of human CRC. Current evidence indicates that overactive mitochondria and hyperactivation of the Rictor-mTORC2-AKT signaling pathway drive key metastatic players and support the formation and progression of metastatic cells in diverse malignant tumors, including early-onset CRC. Small molecule inhibitors that selectively interfere with these key metastatic pathways have become a primary focus of targeted therapy as they control proteins involved in tumor dissemination without affecting normal cells. Selective mTORC2 inhibitors are becoming a potential optimal treatment strategy for patients with CRC because they eliminate therapeutic limitations and drug resistance reported for mTORC1 and mTORC1/mTORC2 inhibitors. Veratridine (VTD), a lipid-soluble alkaloid extracted from Liliaceae plants, can transcriptionally increase UBXN2A, a ubiquitin-like protein. UBXN2A's E3 ubiquitin ligase partners enable UBXN2A to target dually and selectively induce 26S proteasomal degradation of the following substrates: mitochondrial HSP70 (mortalin) proteins and Rictor in the mTORC2 signaling pathway. This study explains the dual-action molecular mechanisms of the VTD-UBXN2A axis in patient-derived xenograft (PDX) cell lines. Longitudinal analysis of cells after completing real-time cell analysis using xCELLigence technology and generating a 3D spheroid CRC model using PDX cells indicate that VTD can effectively restrict cell migration. Additionally, Seahorse bioenergetic assays showed that VTD reduces mitochondria respiration and glycolysis. These results indicate the dual-targeting efficiency of VTD on metastatic cancer cells. This study opened a new platform for repurposing VTD, a supplemental anti-hypertension molecule, into an effective targeted therapy in CRC tumors. Citation Format: Morgan Eikanger, Khosrow Rezvani. Killing two birds with one stone: veratridine functions as a dual inhibitor of both hyperactive mTORC2 and mitochondria in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3027.