BPS2026 – Curved adhesions resist disruption by high-affinity αv integrin inhibitors

Integrins are transmembrane adhesion receptors and important therapeutic targets in cancer and fibrotic diseases. High-affinity αv integrin inhibitors, such as cilengitide and MK-0429, have been developed to block integrin-mediated cell adhesion. These inhibitors effectively disrupt integrin-mediated focal adhesions and detach cells from flat, ligand-coated substrates. However, in this study, we reveal that they are ineffective against curved adhesions, a newly identified class of integrin-based adhesion structures that form in response to membrane curvature. These inhibitors induce focal adhesion disassembly by blocking mechanical force transmission, but curved adhesions form under low mechanical tension and are resistant to this mode of inhibition. As a result, these inhibitors also fail to prevent cancer cell invasion into soft, fibrous 3D extracellular matrices, a process dependent on curved adhesions. These findings reveal a critical limitation of current integrin-targeting strategies and may help explain the clinical failure of drugs like cilengitide.