Targeting ABCA1 via Extracellular vesicle-Encapsulated Staurosporine as a Therapeutic Strategy to enhance Radiosensitivity.

Abstract

Cancer stem cells (CSCs) are essential for tumor initiation, recurrence, metastasis, and resistance. However, targeting CSCs as a therapeutic approach remains challenging. Here, a stemness signature based on 22-gene is developed to predict prognosis in esophageal squamous cell carcinoma (ESCC). Staurosporine (STS) was identified as a radioresistance suppressor by high-throughput screening of a library of 2131 natural compounds, leading to dramatically improved radiotherapy efficacy in subcutaneous tumor models. Mechanistically, STS inhibited cell proliferation through the mTOR/AKT signaling pathway and suppressed stemness by targeting ATP-binding cassette A1 (ABCA1), which is transcriptionally regulated by liver X receptor alpha (LXRα). STS can selectively bind to the nucleotide-binding domain (NBD) of ABCA1 and compete for ATP, blocking ABCA1-mediated drug efflux and facilitating intracellular accumulation of STS. Considering the cytotoxicity of STS, an extracellular vesicle-encapsulated STS system (EV-STS) was established for effective STS delivery. EV-STS showed remarkable tumor growth inhibition, even at half the dose of STS, with superior safety and efficacy. These findings indicate that ABCA1 may serve as a predictor of response to neoadjuvant chemotherapy and/or radiotherapy in ESCC patients. EV-STS has shown improved antitumor efficacy and low systemic toxicity, offering a promising therapeutic approach for ESCC. A 22-gene stemness score predicts prognosis in esophageal squamous cell carcinoma (ESCC). Therefore, we identified staurosporine (STS) by high-throughput screening to suppress stemness. STS overcomes radioresistance by targeting ABCA1. Considering the cytotoxicity of STS, we developed an extracellular vesicle-encapsulated STS system (EV-STS) with superior safety and higher drug delivery efficacy to achieve tumor growth inhibition. This article is protected by copyright. All rights reserved.