# An FAK Kinase/Scaffold Mode-Switch in Dormancy and Resistance

## TL;DR

This paper explores how FAK protein switches between two modes to help dormant cancer cells survive treatment and later regrow, suggesting new therapies that degrade FAK could improve cancer outcomes.

## Contribution

The paper introduces a novel conceptual framework of FAK as a mode-switch between kinase and scaffold functions, linking it to cancer dormancy and resistance.

## Key findings

- FAK's kinase activity (Mode I) promotes cancer cell reactivation and growth.
- FAK's scaffold function (Mode II) protects dormant cells and is not targeted by current inhibitors.
- PROTACs that degrade FAK may be needed to eliminate persistent cancer cells.

## Abstract

Cancer recurrence often occurs because “dormant” tumor cells stop dividing to survive chemotherapy and reactivate later. This process involves Focal Adhesion Kinase (FAK) and its partner YAP. In this review, we propose that FAK acts as a functional switch: “Mode I” drives reactivation and cell growth, while “Mode II” acts as a structural shield that protects dormant cells. Most approved FAK inhibitors target only its kinase activity (Mode I) and do not dismantle the scaffold-dependent survival architecture (Mode II). We suggest that next-generation therapies capable of degrading the FAK protein entirely (PROTACs) may be required to remove this shield and eliminate persistent cancer cells.

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.