# Inhibition of focal adhesion kinase impairs tumor formation and preserves hearing in a murine model of NF2-related schwannomatosis **Authors:** Dana K. Mitchell, Kylee Brewster, Li Jiang, Henry Mang, Waylan K. Bessler, Xiaohong Li, Qingbo Lu, Shaomin Qian, Eric York, Sarah K. Morrow, Shelley A. H. Dixon, Christopher Davis, Ka-Kui Chan, Abbi Smith, Alyssa C. Flint, Victor V. Le, Anna Geisinger, Francis Enane, Behnam Nabet, Steven D. Rhodes, Steven P. Angus, D. Wade Clapp PMC · DOI: 10.1126/sciadv.ady8382 · Science Advances · 2026-01-30 ## TL;DR Inhibiting focal adhesion kinase (FAK) reduces tumor growth and preserves hearing in a mouse model of NF2-related schwannomatosis. ## Contribution The study identifies FAK inhibition as a potential therapeutic strategy for NF2-related schwannomatosis. ## Key findings - Genetic ablation of FAK impairs tumor formation and preserves hearing in a murine model of NF2. - Combining FAK inhibition with MEK inhibition significantly reduces tumor volume and preserves ganglion architecture. - FAK deletion suppresses the HGF-MET axis and reduces inflammasome activation. ## 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. Inhibition of focal adhesion kinase (FAK) impairs schwannoma formation and preserves hearing in an NF2 mouse model. ## Linked entities - **Genes:** NF2 (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) [NCBI Gene 4771], NOD2 (nucleotide binding oligomerization domain containing 2) [NCBI Gene 64127], LRR (Leucine-rich repeat) [NCBI Gene 35715], pyd (polychaetoid) [NCBI Gene 41062], MET (MET proto-oncogene, receptor tyrosine kinase) [NCBI Gene 4233] - **Chemicals:** VS-4718 (PubChem CID 25073775), selumetinib (PubChem CID 10127622) - **Diseases:** NF2-related schwannomatosis (MONDO:0007039), schwannoma (MONDO:0002546) ## Full-text entities - **Genes:** SLTM (SAFB like transcription modulator) [NCBI Gene 79811] {aka Met}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, Eif2ak3 (eukaryotic translation initiation factor 2 alpha kinase 3) [NCBI Gene 13666] {aka Pek, Perk}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Pcna (proliferating cell nuclear antigen) [NCBI Gene 18538], NF2 (NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor) [NCBI Gene 4771] {aka ACN, BANF, SCH, SWNV, merlin-1}, Spint1 (serine protease inhibitor, Kunitz type 1) [NCBI Gene 20732] {aka HAI-1}, PTK2 (protein tyrosine kinase 2) [NCBI Gene 5747] {aka FADK, FADK 1, FAK, FAK1, FRNK, PPP1R71}, Cxcl3 (C-X-C motif chemokine ligand 3) [NCBI Gene 330122] {aka Dcip1, Gm1960}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, Mki67 (antigen identified by monoclonal antibody Ki 67) [NCBI Gene 17345] {aka D630048A14Rik, Ki-67, Ki67}, Parp1 (poly (ADP-ribose) polymerase family, member 1) [NCBI Gene 11545] {aka 5830444G22Rik, ARTD1, Adprp, Adprt1, PARP, PPOL}, Mogat1 (monoacylglycerol O-acyltransferase 1) [NCBI Gene 68393] {aka 0610030A14Rik, 1110064N14Rik, Dgat2l, Dgat2l1, MGAT1, WI1-2612I11.1}, Hgfac (hepatocyte growth factor activator) [NCBI Gene 54426] {aka HGFA}, Ephb2 (Eph receptor B2) [NCBI Gene 13844] {aka Cek5, Drt, ETECK, Erk, Hek5, Nuk}, Vcl (vinculin) [NCBI Gene 22330] {aka 9430097D22}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, Alk (anaplastic lymphoma kinase) [NCBI Gene 11682] {aka CD246, Tcrz}, HGF (hepatocyte growth factor) [NCBI Gene 3082] {aka DFNB39, F-TCF, HGFB, HPTA, SF}, EPHB2 (EPH receptor B2) [NCBI Gene 2048] {aka BDPLT22, CAPB, DRT, EK5, EPHT3, ERK}, Nf2 (neurofibromin 2) [NCBI Gene 18016] {aka merlin}, Itgam (integrin alpha M) [NCBI Gene 16409] {aka CD11b/CD18, CR3, CR3A, Cd11b, F730045J24Rik, Ly-40}, Nod2 (nucleotide-binding oligomerization domain containing 2) [NCBI Gene 257632] {aka ACUG, BLAU, CD, Card15, F830032C23Rik, IBD1}, Mdk (midkine) [NCBI Gene 17242] {aka MK, Mek}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, Cd68 (CD68 antigen) [NCBI Gene 12514] {aka Lamp4, Scard1, gp110}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, Lgals2 (lectin, galactose-binding, soluble 2) [NCBI Gene 107753] {aka 2200008F12Rik}, Casp3 (caspase 3) [NCBI Gene 12367] {aka A830040C14Rik, AC-3, CASP-3, CC3, CPP-32, CPP32}, Hgf (hepatocyte growth factor) [NCBI Gene 15234] {aka C230052L06Rik, HGF/SF, NK1, NK2, SF, SF/HGF}, Mib1 (MIB E3 ubiquitin protein ligase 1) [NCBI Gene 225164] {aka DIP-1, E430019M12Rik, Mib, mindbomb}, H3c7 (H3 clustered histone 7) [NCBI Gene 260423] {aka H3.2-221, H3c13, H3c14, H3c15, H3c2, H3c3}, Ptk2 (PTK2 protein tyrosine kinase 2) [NCBI Gene 14083] {aka FADK 1, FAK, FRNK, Fadk, p125FAK}, Lgals3 (lectin, galactose binding, soluble 3) [NCBI Gene 16854] {aka GBP, L-34, Mac-2, gal3}, Zhx2 (zinc fingers and homeoboxes 2) [NCBI Gene 387609] {aka Afr-1, Afr1, Raf, mKIAA0854}, Ccr5 (C-C motif chemokine receptor 5) [NCBI Gene 12774] {aka AM4-7, CD195, Cmkbr5}, Sox10 (SRY (sex determining region Y)-box 10) [NCBI Gene 20665] {aka Dom, Sox21, gt}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS} - **Diseases:** Tumors (MESH:D009369), ovarian cancer (MESH:D010051), tumorigenic (MESH:D002471), developmental abnormalities (MESH:D006130), bilateral vestibular (VS) and spinal schwannomas (MESH:D009464), melanoma (MESH:D008545), sciatic nerve injury (MESH:D020426), hearing impaired (MESH:D034381), genetic and sporadic disease (MESH:D030342), neuropathic pain (MESH:D009437), cytotoxic (MESH:D064420), lameness (MESH:D007794), MS03 schwannoma (MESH:D009442), demyelination (MESH:D003711), nerve injury (MESH:D000080902), vertigo (MESH:D014717), distress (MESH:D012128), pain (MESH:D010146), inflammation (MESH:D007249), facial paralysis (MESH:D005158), peripheral nerve injury (MESH:D059348), diarrhea (MESH:D003967), deficient (MESH:D007153), neurological deficiencies (MESH:D009461), VS (MESH:D015837), NF2 deficiency (MESH:D016518), schwannomatosis (MESH:C536641), death (MESH:D003643) - **Chemicals:** Cocktail (-), glutamine (MESH:D005973), peptides (MESH:D010455), puromycin (MESH:D011691), 3,3'-Diaminobenzidine (MESH:D015100), Alexa Fluor 647 (MESH:C569686), xylene (MESH:D014992), b (MESH:D001895), Brigatinib (MESH:C000598580), crizotinib (MESH:D000077547), Alexa Fluor 488 (MESH:C000711379), defactinib (MESH:C584510), formalin (MESH:D005557), nitrogen (MESH:D009584), methanol (MESH:D000432), 4',6-diamidino-2-phenylindole (MESH:C007293), formic acid (MESH:C030544), HCl (MESH:D006851), AZD6244 (MESH:C517975), NaF (MESH:D012969), paraffin (MESH:D010232), Plasmocin (MESH:C554844), xylazine (MESH:D014991), avutometinib (MESH:C577924), methylene blue (MESH:D008751), Hepes (MESH:D006531), alcohols (MESH:D000438), Bis-Tris (MESH:C026272), hydrogen peroxide (MESH:D006861), H2O. (MESH:D014867), NaCl (MESH:D012965), Triton X-100 (MESH:D017830), Tween-20 (MESH:D011136), penicillin (MESH:D010406), streptomycin (MESH:D013307), ethanol (MESH:D000431), EDTA (MESH:D004492), GSK2256098 (MESH:C000600809), DMSO (MESH:D004121), EGTA (MESH:D004533), H&E (MESH:D006371), polyvinylidene difluoride (MESH:C024865) - **Species:** Mycoplasma (genus) [taxon 2093], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** A to C, serine/threonine, V600E, G to I, E to H - **Cell lines:** MS03 — Homo sapiens (Human), Melanoma, Cancer cell line (CVCL_C6NK), 02.3 — Homo sapiens (Human), Melanoma, Cancer cell line (CVCL_VU41), MS03s — Mus musculus (Mouse), Hybridoma (CVCL_U609), hTERT ipn02.3 — Homo sapiens (Human), Telomerase immortalized cell line (CVCL_UI64), LM22 — Homo sapiens (Human), Astrocytoma, Cancer cell line (CVCL_A1IU), HEI-193 — Homo sapiens (Human), Neurofibromatosis type 2, Transformed cell line (CVCL_7670) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12857737/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12857737/full.md ## References 99 references — full list in the complete paper: https://tomesphere.com/paper/PMC12857737/full.md --- Source: https://tomesphere.com/paper/PMC12857737