EPHA2 is a Potential Target for the Treatment of NF2-/-Vestibular Schwannoma

Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas secondary to loss heterozygosity NF2 in Schwann cells or their precursors. While these tumors are largely benign, they can cause considerable morbidity due compromised auditory, vestibular, facial, vertebral nerve function. This may result deafness, vertigo, facial muscle weakness, chronic neuropathic pain, even death.There currently no pharmacotherapies for VS, surgical resection remains standard care, which associated with significant morbidity. Thus, there urgent need develop pharmaceutical approaches halt reverse progression tumor growth patients who VS. Our lab previously identified receptor tyrosine kinase inhibitors brigatinib dasatinib as potentially efficacious agents treatment VS demonstrated that both targeted Ephrin A2 (EPHA2). EPHA2is a transmembrane thatis involved cell contact-mediated motility, adhesion,and migration. Additionally, EPHA2 modulates axon guidance, synaptogenesis developing brain. Here we demonstrate EPHA2expression increased NF2-/-Schwanncells NF2-/-cancers. We identify ponatinib, inhibitor targeting ABL1 FDA-approved CML, additional agent targets EPHA2. ponatinib impairs viability human murine vitro decreases protein expression. Accordingly, pharmacologic,and siRNA-mediated inhibition also impaired NF2-/-Schwann vitro. Lastly, induce morphological changes cells. findings suggest direct be NF2-associated schwannoma. Future vivo efficacystudies warranted.