# Targeting the MAPK Pathway in Brain Tumors: Mechanisms and Therapeutic Opportunities

## TL;DR

This review explores how the MAPK pathway contributes to brain tumors and discusses current and future therapies targeting this pathway to improve treatment outcomes.

## Contribution

The paper provides a comprehensive synthesis of MAPK pathway alterations and therapeutic strategies in CNS tumors, emphasizing precision treatment approaches.

## Key findings

- MAPK pathway dysregulation is a common feature in many pediatric and adult CNS tumors.
- Therapies targeting the MAPK pathway face challenges like drug resistance and limited BBB penetration.
- Combination strategies and novel drug-delivery technologies are being explored to enhance treatment efficacy.

## Abstract

Brain tumors remain among the most difficult cancers to treat, largely because of their biological complexity and the limited ability of many drugs to reach the brain. A major molecular pathway that drives the growth of many brain tumors is the MAPK signaling pathway. In this review, we explain how alterations in this pathway contribute to tumor development in both children and adults, and we summarize current and emerging therapies that specifically target this pathway. We also discuss the main challenges that limit treatment success, including drug resistance, tumor diversity, and the protective blood–brain barrier. By integrating recent advances in molecular biology with therapeutic strategies, this work aims to guide future research and improve precision treatment approaches for patients with brain tumors.

Central nervous system (CNS) tumors consist of a diverse set of malignancies that remain clinically challenging due to their biological complexity, high morbidity, and limited responsiveness to current therapies. A growing body of genomic evidence has revealed that dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway is a recurrent and unifying characteristic across many pediatric and adult CNS tumor entities. Alterations affecting upstream receptor tyrosine kinases (RTKs), RAS GTPases, RAF kinases, and other associated regulators contribute to MAPK signaling pathway hyperactivation, shaping tumor behavior, therapy response and resistance. These aberrations ranging from hotspot mutations such as BRAF V600E and oncogenic fusions like BRAF–KIAA1549 are particularly enriched in gliomas and glioneuronal tumors, highlighting MAPK signaling as a key oncogenic driver. The expanding availability of molecularly targeted compounds, including selective inhibitors of RAF, MEK and ERK, has begun to transform treatment approaches for specific molecular subtypes. However, the clinical benefit of MAPK-directed therapies is frequently limited by restricted blood–brain barrier (BBB) penetration, intratumoral heterogeneity, parallel pathway reactivation, and an immunosuppressive tumor microenvironment (TME). In this review, we synthesize current knowledge on MAPK pathway alterations in CNS tumors and evaluate the therapeutic landscape of MAPK inhibition, with emphasis on approved agents, emerging compounds, combination strategies, and novel drug-delivery technologies. We also discuss mechanisms that undermine treatment efficacy and highlight future directions aimed at integrating MAPK-targeted therapy into precision-based management of brain tumors.