Curved adhesions resist disruption by high-affinity αv-integrin inhibitors.

Integrins are transmembrane adhesion receptors and major therapeutic targets in cancer and fibrotic diseases. High-affinity αv-integrin inhibitors, including cilengitide and MK-0429, were developed to block integrin-dependent cell adhesions. These inhibitors have been shown to disrupt integrin-mediated focal adhesions on flat, ligand-coated surfaces. Here, we demonstrate that these inhibitors are ineffective against curved adhesions, a class of integrin-mediated adhesion structures that assemble in response to membrane curvature. We find that, unlike focal adhesions, curved adhesions form under low mechanical tension, rendering them resistant to these inhibitors that act by blocking force transmission. As a result, these inhibitors also do not prevent cancer cell invasion into soft, fibrous three-dimensional extracellular matrices, a process that depends on curved adhesions. These findings expose a limitation of current integrin-targeting strategies and may help explain why some inhibitors have underperformed in clinical trials.