Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer. (October 2022)

• Record Type: Journal Article
• Authors: Cho, Young Seok; Kim, Ha Rin; Park, Seong Jin; Chung, Seung Woo; Ko, Yoon Gun; Yeo, Joo Hye; Lee, Jinu; Kim, Sang Kyoon; Choi, Jeong Uk; Kim, Sang Yoon; Byun, Youngro
• Is Part Of: Biomaterials. Volume 289(2022)
• Publication Date: 2022-10
• Subjects: PTEN-Loss -- Macropinocytosis -- Bystander killing -- Caspase-3 -- Peptide-drug conjugate -- Metastatic triple-negative breast cancer; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2022.121783
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy. Graphical abstract: Image 1