Presently, an FDA-approved medical therapy for the treatment of NF2-deficient meningiomas is not available. To identify novel targeted therapies for these tumors, we, as members of the Synodos for NF2 Consortium, in collaboration with the National Center for Advancing Translational Sciences (NCATS), identified Brigatinib, a potent inhibitor of anaplastic lymphoma kinase(ALK) and other receptor tyrosine kinases (RTKs), to be effective as a single agent in inhibiting proliferation of NF2-deficientmeningioma cells and suppressing tumor growth in an orthotopic NF2-deficient meningioma animal model. Additionally, we showed that INK-128, a dual mTORC1/2 inhibitor, synergized with Brigatinib to potently suppress meningioma cell proliferation in vitro. Based on these data, we have proposed to evaluate the Brigatinib/INK-128 combination as an effective treatment forNF2-deficient meningiomas and investigate their mechanisms of action. We have found that NF2-deficient meningiomas did not express ALK and that Brigatinib potently suppressed the growth of NF2-deficient tumors via inhibition of multiple RTKs and non-RTKs, such as focal adhesion kinase (FAK). These findings have led to a phase II clinical trial to evaluate Brigatinib inpatients with NF2 with associated progressive tumors of vestibular schwannomas, non-vestibular schwannomas, meningiomas, and ependymomas. Also, we showed that in addition to NF2-deficient meningioma, Brigatinib had anti-tumor efficacy against and NF1-deficient MPNST, suggest that Brigatinib may also be a viable treatment for MPNST. Intriguingly, combination of Brigatinib with the dual MTORC1/2 inhibitor INK128 only modestly enhances the anti-tumor effects. In addition, we have generated an NF2-associated meningioma cell line AG-NF2-Men-1. Luciferase-expressing AG-NF2-Men-1 cells are being used to establish an orthotopic NF2-associated meningioma model for drug evaluation.