Abstract 2939: The effect of cSNX1.3 on MMTV-PyMT tumor growth and metastasis

Abstract The Epidermal Growth Factor Receptor (EGFR) belongs to a group of Receptor Tyrosine Kinases (RTKs) that are a part of the HER family. EGFR mediates many processes in the cell including proliferation, migration, and survival however its overexpression is correlated with poor prognosis in several epithelial cancers including Triple Negative Breast Cancer (TNBC). In healthy cells, EGF binds to EGFR dimerizes and undergoes transphosphorylation, and can then be intracellularly imported where it is taken to the early endosome and awaits ubiquitination. This signals readiness to be taken to the lysosome where it undergoes degradation or in some cases, gets recycled. In cancerous cells, however, ubiquitination gets inhibited due to their loss of polarity. This results in failure to signify readiness to be taken to the lysosome which allows EGFR to completely evade degradation and undergo nuclear localization. This process is initiated by the binding of Sorting Nexin 1 (SNX1), a protein responsible for the regulation of trafficking, to EGFR. Considering the interaction between Sorting Nexins and RTKs causes oncogenic activity, it was hypothesized in this lab that a therapeutic that can modify this interaction can alter tumor-specific retrotranslocation. In order to target these interactions, the therapeutic peptide, cSNX1.3, was developed. cSNX1.3 is a cell-penetrating peptide with a Protein Transduction Domain that allows for the delivery of peptides across the cell membrane and into the intracellular domain. cSNX1.3 interacts with EGFR when it’s in the long-lived endosome and binds in competition with SNX1. When cSNX1.3 is bound to EGFR, it is able to inhibit the nuclear localization of the RTK and as a result, inhibit its oncogenic activity. In order to fully evaluate the tumor-regressing abilities of cSNX1.3, we used an immunocompetent model of transgenic Whey Acidic Protein - Transforming Growth Factor alpha (WAP-TGFα) mice, whose mammary gland tumors are EGFR dependent. These mice were treated with cSNX1.3 or the control drug, cPTD4, over the course of 4 weeks. After completion of treatment, it was determined that the tumors of the cPTD4-treated mice continued to grow whereas the tumors of the cSNX1.3-treated mice began to regress. We then decided to construct an additional study using another immunocompetent mouse model that would also demonstrate how cancer metastasis reacted to cSNX1.3 treatment, given that metastasis is typically what makes breast cancer fatal in humans. For these reasons, we decided to use a model of transgenic Mouse Mammary Tumor Virus - Polyoma Middle T (MMTV-PyMT) mice. Conducting an evaluation of cSNX1.3 using this model that closely resembles the function of metastatic breast cancer in humans, will allow us to better understand the future of cSNX1.3 as a breast cancer therapeutic for human applications. Citation Format: Delina J. Denogean, Barbara Sands, Joyce Schroeder. The effect of cSNX1.3 on MMTV-PyMT tumor growth and metastasis [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 2939.