Abstract PS3-13-15: Dasatinib-induced Src inhibition blocks nonangiogenic vascularization and potentiates antibody-drug conjugates in high-grade breast cancer

Abstract Background: Nonangiogenic vascularization (NAV)—encompassing vascular mimicry (VM) and vessel cooption (VCO)—allows high-grade breast cancers to secure a blood supply and evade antiangiogenic therapy. We aimed to identify a small-molecule inhibitor that disrupts NAV. Methods: A library of 259 clinically relevant compounds was screened using VM tube formation assays in trastuzumab-resistant, HER2-positive JIMT-1 cells and triple-negative MDA-MB-231 cells. VCO was evaluated by the adhesion of cancer cells to preformed human umbilical vein endothelial cell tubes. Mechanistic studies involved Src pathway immunoblotting and siRNA knockdown. Antitumor efficacy was evaluated in orthotopic xenografts, with vasculature characterized by mouse CD31, mouse CD105, and human SERPINE2 immunostaining and apoptosis evaluated by TUNEL assay. Combination studies with trastuzumab-emtansine (T-DM1) were conducted in the JIMT-1 model. Results: Three Src inhibitors—dasatinib, bosutinib, and ponatinib—emerged as potent VM inhibitors, with dasatinib being the most active (IC50 = 1.4 nM in JIMT-1 cells; 7.3 nM in MDA-MB-231 cells). Dasatinib also abrogated VCO, and Src knockdown phenocopied its effects, confirming pathway dependence. In vivo, dasatinib significantly reduced tumor growth without increasing the number of TUNEL-positive cells; however, it markedly depleted the number of CD31-positive mature vessels and SerpinE2-positive tumor cells but spared CD105-positive immature vessels. Dasatinib improved the antitumor activity of T-DM1; specifically, the combination further suppressed CD31-positive vasculature. Conclusions: Dasatinib disrupts NAV by targeting Src, translating into tumor growth inhibition and improved efficacy of T-DM1 therapy. These results support repurposing dasatinib to overcome NAV-mediated therapeutic resistance in high-grade breast cancer. Citation Format: M. Shimoda, I. Seto, M. Masuyama, K. Kikumori, K. Shimazu. Dasatinib-induced Src inhibition blocks nonangiogenic vascularization and potentiates antibody-drug conjugates in high-grade breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-15.