Context-specific targeting of focal adhesion kinase in brain tumors: lessons from glioblastoma and neurofibromatosis type 2-mutant meningioma

Focal adhesion kinase (FAK) has long been explored as a therapeutic target in glioblastoma (GBM) based on its overexpression and involvement in invasive signaling. However, clinical trials have consistently failed to show benefit - highlighting a core principle of translational oncology: target presence alone does not imply therapeutic relevance. In contrast, neurofibromatosis type 2 (<i>NF2</i>)-mutant meningiomas present a biologically grounded vulnerability, in which loss of the tumor suppressor moesin-ezrin-radixin-like protein (merlin) creates a synthetic lethal dependency on FAK. This context-specific dependency enables clinically meaningful targeting. Early-phase trials already show promising disease control with favorable safety profiles. This mini review examines the contrasting roles of FAK in GBM and <i>NF2</i>-mutant meningiomas to underscore the importance of biological context in therapeutic decisions. We propose that <i>NF2</i>-mutant meningiomas represent a model for context-specific, synthetic lethal targeting, exemplifying a functional oncogenomics approach to precision oncology.