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Updated: Mar 29, 2026

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

Changchang Sun1, Qiuting Feng1, Yiyang Zhao1

  • 1Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Cancers
|March 28, 2026
PubMed

Insights

Late relapsing cancers are driven by dormant cells. Targeting focal adhesion kinase (FAK) functional modes, not just its activity, may eliminate these persistent cells and prevent relapse.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Therapeutics

Background:

  • Late relapses in cancer are often caused by dormant tumor cells and drug-tolerant persisters (DTPs).
  • Focal adhesion kinase (FAK) and YAP/TAZ are key regulators of cell survival, quiescence, and reactivation, integrating mechanical cues with stress signaling.
  • Current ATP-competitive FAK inhibitors incompletely eradicate persister cells, suggesting limitations in targeting FAK activity alone.

Purpose of the Study:

  • To propose a "Mode-Switch" model for FAK function in cancer persister cells.
  • To explain the incomplete efficacy of ATP-competitive FAK inhibitors against persister reservoirs.
  • To motivate novel therapeutic strategies targeting FAK protein stability or downstream signaling pathways.

Main Methods:

  • Conceptual framework development based on existing literature.
  • Analysis of FAK signaling in relation to cell persistence and reactivation.
  • Proposal of pathology-compatible proxies for FAK functional mode assessment (pY397-FAK/total FAK, localization, YAP/TAZ/TEAD activity).

Main Results:

  • FAK operates in at least two functional modes: Mode I (kinase-dependent, promoting regrowth) and Mode II (kinase-independent, sustaining persistence).
  • The "Mode-Switch" model explains why inhibiting FAK activity alone is insufficient to eliminate persister cells.
  • Composite readouts can potentially distinguish between these FAK functional modes.

Conclusions:

  • Targeting FAK's functional modes, rather than just its kinase activity, is crucial for eradicating cancer persister cells.
  • Strategies like FAK degradation or YAP/TEAD blockade may be effective in dismantling persister reservoirs.
  • A framework for biomarker-stratified intervention in minimal residual disease is proposed, matching therapeutic modality to dominant FAK functional mode.
Keywords:
Cancer dormancyDrug resistanceFocal adhesion kinase (FAK)PROTACsYes-associated protein (YAP)

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