2. Academic Validation
  3. Inhibition of focal adhesion kinase impairs tumor formation and preserves hearing in a murine model of NF2-related schwannomatosis

Inhibition of focal adhesion kinase impairs tumor formation and preserves hearing in a murine model of NF2-related schwannomatosis

  • Sci Adv. 2026 Jan 30;12(5):eady8382. doi: 10.1126/sciadv.ady8382.
Dana K Mitchell 1,  Kylee Brewster 1,  Li Jiang 1,  Henry Mang 1,  Waylan K Bessler 1,  Xiaohong Li 1,  Qingbo Lu 1,  Shaomin Qian 1,  Eric York 1,  Sarah K Morrow 1,  Shelley A H Dixon 1,  Christopher Davis 1,  Ka-Kui Chan 1,  Abbi Smith 1,  Alyssa C Flint 1,  Victor V Le 1,  Anna Geisinger 2,  Francis Enane 2,  Behnam Nabet 3 4,  Steven D Rhodes 1 5 6 7,  Steven P Angus 1 7 8 9,  D Wade Clapp 1 5 7 9
Affiliations

Affiliations

  • 1 Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 2 Indiana Biosciences Research Institute, Indianapolis, IN, USA.
  • 3 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 4 Department of Pharmacology, University of Washington, Seattle, WA, USA.
  • 5 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 6 Division of Pediatric Hematology/Oncology/Stem Cell Transplant, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 7 IU Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 8 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 9 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
PMID: 41616055 DOI: 10.1126/sciadv.ady8382
Abstract

NF2 (neurofibromatosis type 2)-related schwannomatosis (NF2-SWN) is a Cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas. While benign, these tumors can cause substantial morbidity, and effective pharmacological treatments remain limited. Here, we demonstrate that genetic ablation of focal adhesion kinase (FAK/Ptk2) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that FAK deletion decreases macrophage infiltration, attenuates nucleotide-binding oligomerization domain-containing protein 2-, leucine rich repeats (LRR)- and pyrin domain-containing protein 3 inflammasome activation, and suppresses the hepatocyte growth factor-MET axis. Pharmacological inhibition of FAK with single agent VS-4718 did not significantly reduce macroscopic tumor volume; however, its use in combination with the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib resulted in both a significant reduction in tumor volume and the preservation of dorsal root ganglion architecture. Our findings establish a critical role for FAK in schwannoma development and provide rationale for evaluation of combination FAK plus MEK inhibition in future clinical trials for NF2-associated SWN.

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