Authors: Fatma Kazdal, Nermin Kahraman, Bulent Ozpolat
Published: 2025-04-21
DOI: 10.1158/1538-7445.am2025-1860
Source: Full article
Triple Negative Breast Cancer (TNBC) is the most aggressive and heterogeneous subtype of breast cancer with the highest mortality rates. TNBC is characterized by a lack of Estrogen (ER), PR, and HER2 receptors and currently, there is no effective targeted therapy for TNBC patients. AXL, a receptor tyrosine kinase (AXL-RTK), is overexpressed in TNBC cells and patient tumors and has been linked to poor prognosis. Despite its potential as a therapeutic target, there are currently no FDA-approved inhibitors for AXL in TNBC. In this study, we aimed to develop AXL- inhibitor-based targeted therapy and evaluate its therapeutic potential for TNBC using a PLGA (poly-lactic-co-glycolic acid)) nanoparticle delivery system. We formulated it into PLGA nanoparticles to improve bioavailability and enable targeted delivery to TNBC tumors. Various dosages of AXL inhibitor-loaded PLGA nanoparticles were tested on MDA-MB-231 and MDA-MB-436 human TNBC cell lines, and significant inhibition of cell growth and colony formation was observed, with a half-maximal inhibitory concentration (IC50) of 5 μM. The size and morphology of the nanoparticles were characterized using Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM), which revealed nanoparticle sizes ranging from 63-99.9 nm. Western blot analysis showed that the AXL inhibitor-loaded PLGA nanoparticles effectively inhibited AXL protein expression and its downstream signaling pathways, leading to superior anti-proliferative effects compared to free AXL inhibitors. These results suggest that AXL inhibitor-loaded PLGA nanoparticles offer a promising strategy for enhancing the therapeutic efficacy of AXL inhibitors in TNBC. In vivo, efficacy studies are currently underway to evaluate their potential for targeted therapy in both primary and metastatic TNBC models.