(93d) Identification of GPNMB Specific Binder for Overcoming Drug Resistance in ER+ Breast Cancer

Cancer drug resistance remains a major challenge in cancer therapy, contributing to relapse and metastasis. Recently, glycoprotein non-metastatic melanoma protein B (GPNMB) has emerged as a promising therapeutic target for overcoming drug resistance. However, specific compounds targeting GPNMB are currently unavailable. In this study, we report the identification and functional analysis of potential drug candidates using a novel magnetic drug-screening platform. This nanoplatform utilizes cell membrane-coated magnetic nanoparticles with immobilized GPNMB as the screening target. We employed LCC-2 cells overexpressing GPNMB as a model system to identify clinically relevant GPNMB binders. Screening the NIH Clinical Collection library revealed several small-molecule binders with high binding affinity to GPNMB, including epigallocatechin gallate (EGCG), a natural polyphenol compound. The binding affinity of the identified GPNMB binders were quantified by molecular simulations and isothermal titration calorimetry (ITC). Preliminary evaluations in multiple drug-resistant cell lines suggest three compounds had great promise to overcome drug resistance. Our findings demonstrate the feasibility of identifying small-molecule modulators of GPNMB with potential therapeutic applications in addressing drug resistance in ER+ breast cancers.