An FAK kinase/scaffold mode-switch in dormancy and resistance

Late relapses are one of the most frustrating aspects of cancer treatment. They are frequently driven by dormant tumor cells and drug-tolerant persisters (DTPs) that survive therapy and later re-enter proliferation. Focal adhesion kinase (FAK) and the mechanosensitive transcriptional co-activators YAP/TAZ integrate extracellular matrix mechanics with intracellular stress signaling to coordinate survival, quiescence and reactivation. We propose that the key determinant is often not “FAK on/off”, but functional mode selection between (Mode I) kinase-dependent signaling bursts linked to adhesion remodeling and regrowth and (Mode II) kinase-independent scaffolding and non-canonical localization (including nuclear pools) that sustain a persistence architecture under stress. This Mode-Switch lens helps explain why ATP-competitive FAK inhibitors can suppress pY397-FAK-dependent outputs yet incompletely eradicate persister reservoirs and motivates strategies that remove FAK protein or disrupt persistence circuitry. We outline operational, pathology-compatible proxies for assigning dominant mode using composite readouts of pY397-FAK/total FAK, FAK localization, and YAP/TAZ/TEAD executor output. Finally, we discuss modality matching—kinase inhibition to suppress regrowth versus FAK degradation and/or YAP/TEAD blockade to dismantle persister reservoirs—as a testable framework for biomarker-stratified intervention in minimal residual disease.