Effect of Fak1/Ptk2 knockout in a mouse model of NF2-related schwannomatosis

NF2-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 significant morbidity and effective pharmacological treatments remain limited. Here we demonstrate that genetic ablation of focal adhesion kinase 1 (FAK1/PTK2) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that Fak1 deletion decreases macrophage infiltration, attenuates NLRP3 inflammasome activation and suppresses the HGF-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 MEK inhibitor selumetinib resulted in both a significant reduction tumor volume and the preservation of dorsal root ganglion (DRG) 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 schwannomas. Overall design: Dorsal root ganglia (8 per mouse) tissue was microdissected from 10-month old euthanized Postn-Cre(+);Nf2 flox/flox animals (n=6, 3 male, 3 female) and from Postn-Cre(+);Nf2 flox/flox;Fak1 flox/flox (double knockout, DKO) animals(n=6, 3 male, 3 female), flash frozen and sent to Azenta/GenWiz for mRNA sequencing.