Inhibition of Anaplastic Lymphoma Kinase (Alk) as Therapeutic Target to Improve Brain Function in Neurofibromatosis Type 1 (Nf1)

SIMPLE SUMMARY: Neurofibromatosis type 1 (Nf1) is a genetically determined neurodevelopmental disorder and tumor syndrome with an incidence of approximately 1/3000 live births. It is caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Approximately 50% of the patients inherited the condition in an autosomal dominant pattern; the remaining 50% are the result of de novo mutations. Behavioral alterations and cognitive deficits have been found in 50–70% of children with Nf1. These behavioral alterations and cognitive deficits include specific problems with attention, visual perception, language, learning, attention, and executive function. Inhibition of the anaplastic lymphoma kinase (Alk), a kinase which is negatively regulated by neurofibromin, allows for testing the hypothesis that this inhibition may be therapeutically beneficial in Nf1. In this review, we discuss this area of research and directions for the development of alternative therapeutic strategies to inhibit Alk. ABSTRACT: Neurofibromatosis type 1 (Nf1) is a neurodevelopmental disorder and tumor syndrome caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Behavioral alterations and cognitive deficits have been found in 50–70% of children with Nf1 and include specific problems with attention, visual perception, language, learning, attention, and executive function. These behavioral alterations and cognitive deficits are observed in the absence of tumors or macroscopic structural abnormalities in the central nervous system. No effective treatments for the behavioral and cognitive disabilities of Nf1 exist. Inhibition of the anaplastic lymphoma kinase (Alk), a kinase which is negatively regulated by neurofibromin, allows for testing the hypothesis that this inhibition may be therapeutically beneficial in Nf1. In this review, we discuss this area of research and directions for the development of alternative therapeutic strategies to inhibit Alk. Even if the incidence of adverse reactions of currently available Alk inhibitors was reduced to half the dose, we anticipate that a long-term treatment would pose challenges for efficacy, safety, and tolerability. Therefore, future efforts are warranted to investigate alternative, potentially less toxic and more specific strategies to inhibit Alk function.