Glycomimetic Lysosome-targeting Chimeras (GLYTACs) for Degradation of Growth Factors and Growth Factor Receptors in Cancer Cells

ABSTRACT Many cancers depend on extracellular growth factors within the tumor microenvironment to drive aberrant signaling, proliferation, and survival. For example, anticancer therapies targeting vascular endothelial growth factor activity have been effective in blocking pro-angiogenic and pro-growth signals, including receptor tyrosine kinase inhibitors (e.g., Sunitinib and Sorafenib) and monoclonal antibodies (e.g., Bevacizumab). However, the effectiveness of these therapies is frequently limited by compensatory growth factor signaling and incomplete blockade, contributing to drug resistance and suboptimal long-term responses. To address these challenges, we developed Glycomimetic Lysosome-targeting Chimeras (GLYTACs) that sequester and degrade extracellular growth factors in the cancer cell environment. GLYTACs exploit growth factor interactions with cell-surface heparan sulfate (HS) glycans, a feature shared by many pro-tumorigenic signals and their receptors, by combining an HS-glycomimetic arm for growth factor binding with a polyvalent glycopolymer ligand targeting the lysosomal recycling cation-independent mannose 6-phosphate receptor (CI-M6PR) for efficient internalization and degradation. Treating HeLa cells with a heparin-based GLYTAC prototype drove rapid uptake and degradation of extracellular fibroblast growth factor 2 (FGF2). The capacity of heparin to promote the association of FGF2 with its cognate receptors (FGFRs) led to the degradation of the entire receptor-ligand complex, thereby reducing the availability of FGFRs at the cancer cell surface, which are necessary for sustained pro-oncogenic signaling. These findings highlight the potential of GLYTACs as an alternative to existing growth factor-blocking anticancer therapies and as a strategy to reshape the extracellular signaling environment of tumors.