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

Sep 28, 2026

Uploaded by Eliana

Focal adhesion kinase (FAK) is explored as a therapeutic target in glioblastoma (GBM) due to overexpression and roles in invasive signaling, yet FAK inhibition has not translated into clinical benefit, underscoring that target presence alone cannot establish therapeutic relevance. In contrast, neurofibromatosis type 2 (NF2)-mutant meningiomas show a context-specific vulnerability: loss of merlin creates a synthetic lethal dependency on FAK signaling. Early-phase trials report promising control with favorable safety.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

Translational oncology challenge in target selection

Distinct biological drivers across brain tumor entities

NF2 pathway and merlin loss

Frequency across WHO grades and anatomical enrichment

Synthetic lethal FAK dependency in NF2-mutant meningiomas

TYPE Mini Review PUBLISHED 19 December 2025 DOI 10.3389/fonc.2025.1724278 OPEN ACCESS EDITED BY Raphael Bertani, University of São Paulo, Brazil REVIEWED BY Yogendra Nayak, Manipal University, India Hassan Mumtaz, Resear-Ligent Limited, United Kingdom Sixuan Pan, University of California, San Francisco, United States Deeptarup Biswas, Harvard Medical School, United States Cecilia Krona, Uppsala University, Sweden *CORRESPONDENCE Andre Sagerer [andrenorbertjosef.sagerer@ukdd.de](andrenorbertjosef.sagerer@ukdd.de) RECEIVED 13 October 2025 REVISED 03 December 2025 ACCEPTED 08 December 2025 PUBLISHED 19 December 2025 CITATION Sagerer A, Eyüpoglu IY, Juratli TA and Cordes N (2025) Context-speciﬁc targeting of focal adhesion kinasein brain tumors: lessons from glioblastoma and neuroﬁbromatosis type 2-mutant meningioma. Front. Oncol. 15:1724278 . doi: 10.3389/fonc.2025.1724278 COPYRIGHT © 2025 Sagerer, Eyüpoglu, Juratli and Cordes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Context-speciﬁc targeting of focal adhesion kinase in brain tumors: lessons from glioblastoma and neuroﬁbromatosis type 2-mutant meningioma Andre Sagerer 1,2*, Ilker Y. Eyüpoglu 1,2, Tareq A. Juratli 1,2 and Nils Cordes 2,3,4,5,6 1 Department of Neurosurgery, Medical Faculty and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany, 2 National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany, 3OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, 4 HelmholtzZentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany, 5German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany, 6 Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany 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 (NF2)-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 NF2-mutant meningiomas to underscore the importance of biological context in therapeutic decisions. We propose that NF2-mutant meningiomas represent a model for context-speciﬁc, synthetic lethal targeting, exemplifying a functional oncogenomics approach to precision oncology. KEYWORDS FAK inhibitor, focal adhesion kinase, glioblastoma, NF2-mutant meningioma, pFAKY397, precision oncology, synthetic lethality Frontiers in Oncology 01 [frontiersin.org](frontiersin.org) 1 Introduction Translational oncology often faces a fundamental challenge: therapeutic targets are frequently chosen based on

FAQs

Why did FAK inhibition fail to benefit glioblastoma patients despite strong target rationale?

Clinical trials did not show benefit, illustrating that target expression or known pathway involvement does not guarantee functional dependency required for therapeutic efficacy.

What creates the vulnerability of NF2-mutant meningiomas to FAK targeting?

Loss of the tumor suppressor merlin (in NF2-mutant meningiomas) produces a synthetic lethal dependency on FAK signaling, making the target therapeutically meaningful in that context.

How does the review connect biological context to precision oncology decisions?

It contrasts GBM versus NF2-mutant meningiomas to argue that therapeutic targeting must be guided by context-specific functional dependency, not by target presence alone, aligning with a functional oncogenomics approach.

Sep 28, 2026

Uploaded by Eliana