Lung adenocarcinoma, the predominant subtype of non-small cell lung cancer (NSCLC), is frequently driven by actionable oncogenic mutations. While EGFR mutations are effectively targeted by tyrosine kinase inhibitors (TKIs) such as osimertinib, acquired resistance often develops. The BRAF-V600E mutation has emerged as a key resistance mechanism, shifting the treatment paradigm to alternative targeted therapies (TTs), including dabrafenib and trametinib (1, 2). Brain metastases (BMs) develop in approximately 20-40% of advanced NSCLC patients and are a leading cause of morbidity and mortality, with a median overall survival of less than one year (3, 4). Local radiotherapy (RT), including stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT), remains a cornerstone of BMs management, providing durable local control (5–7). Combining RT with targeted agents has shown promise for improving intracranial control, yet the optimal integration of these modalities remains undefined, particularly for BRAF inhibitors (8, 9).

Complicating this approach is the risk of RN, a serious complication of cranial irradiation characterized by neuroinflammation, blood-brain barrier disruption, and cognitive decline (10–13). The combination of BRAF inhibitors (BRAFi) with radiotherapy (RT) has shown efficacy in controlling BRAF-mutant tumors but is associated with an increased risk of severe radiation necrosis, particularly in the central nervous system (CNS) (14). When BRAFi (especially first-generation inhibitors like vemurafenib) are administered concurrently with RT, they may synergistically disrupt critical pro-survival and repair pathways in the vascular endothelium. Furthermore, the “paradoxical activation” of the MAPK pathway by these inhibitors in cells with wild-type BRAF (such as normal endothelial cells in the irradiated field) may create a pro-inflammatory milieu, enhancing vascular leakage and inflammatory cell recruitment. This combined insult amplifies the cascade of endothelial dysfunction, abnormal angiogenesis, and eventual vessel obliteration, thereby significantly increasing the probability of developing severe, symptomatic RN (15, 16).

This review synthesizes current evidence on the mechanisms and risk factors for RN in patients with BRAF-mutant lung adenocarcinoma receiving combined BRAFi and RT. We highlight the urgent need for multidisciplinary management strategies and future research to optimize therapeutic outcomes while mitigating this debilitating toxicity.

BRAFi are a class of targeted anticancer drugs designed to block the activity of the BRAF kinase, a key component of the MAPK/ERK signaling pathway. This pathway is frequently dysregulated in cancers, most commonly via the BRAF V600E mutation. BRAFi specifically bind to the ATP-binding site of the mutant BRAF kinase, inhibiting its constitutive activity and downstream signaling, leading to cell cycle arrest and apoptosis (17).

It is crucial to distinguish their mode of action regarding wild-type BRAF (BRAF WT). First-generation BRAFi (e.g., vemurafenib, dabrafenib) are considered selective or mutant-selective inhibitors. They potently inhibit monomeric mutant BRAF (especially V600E). However, in cells with active upstream signaling (e.g., RAS activation), they can paradoxically activate the MAPK pathway by promoting dimerization of BRAF WT with CRAF, a phenomenon known as “paradoxical activation” (18). Second-generation “paradox breaker” inhibitors (e.g., PLX8394) are designed to inhibit both mutant and wild-type BRAF without inducing this paradoxical activation (19). Pan-RAF inhibitors (e.g., sorafenib, LY3009120) target all RAF isoforms (ARAF, BRAF, CRAF) regardless of mutation status (20, 21). Table 1 lists the current available BRAFi in market.

RN primarily driven by vascular dysfunction, immune-mediated inflammation, and oxidative stress, all contributing to disruption of the BBB, ischemic injury, and chronic neuroinflammation (24). In which, initiated primarily by radiotherapy-induced disruption of BBB and direct neural cell damage. Ionizing radiation causes structural and functional damage to the BBB by inducing endothelial cell apoptosis, tight junction protein degradation, and increased vascular permeability, leading to leakage of plasma components and infiltration of inflammatory cells into the brain parenchyma (25). This BBB disruption facilitates neuroinflammation and oxidative stress, which are pivotal in the pathogenesis of RN (24). Key molecular pathways involved include VEGF-mediated endothelial damage, cGAS-STING-driven innate immune activation, and radiation-induced mitochondrial dysfunction (13).

Microglial activation is a hallmark of RN, with these resident immune cells releasing pro-inflammatory cytokines such as IL-6, TNF-α, and reactive oxygen species (ROS), exacerbating neuronal injury and perpetuating a vicious cycle of inflammation. Oxidative stress, resulting from excessive ROS production and impaired antioxidant defenses, further damages lipids, proteins, and nucleic acids within neural cells, contributing to cellular dysfunction and death (26, 27).

Several factors influence the risk of RN, including radiation dose, fractionation schedule, and treatment volume. Higher biologically effective doses (BED), larger treatment fields, and retreatment with cumulative doses exceeding 100 Gy increase RN risk (28). Additionally, tumor biology (e.g., BRAF mutations, VEGF overexpression) and patient-specific factors (e.g., age, pre-existing vascular disease) may further predispose individuals to RN (29).

(3) Radiation directly damages vascular endothelial cells, inducing senescence, apoptosis, and increased expression of adhesion molecules (e.g., ICAM-1, VCAM-1). This initiates a chronic state of vascular inflammation and dysfunction. Key alterations include: Loss of nitric oxide (NO) bioavailability, increased oxidative stress, and upregulation of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IFN-γ). Disruption of tight junctions and the basement membrane increases permeability. Radiation promotes the expression of VEGF and other angiogenic factors as a compensatory response. However, the newly formed vessels are often abnormal—dilated, tortuous, and leaky—with poor pericyte coverage, failing to restore proper perfusion. Chronic inflammation leads to vessel wall thickening, hyalinization, and thrombosis, culminating in reduced vascular density and tissue ischemia. The persistent release of TGF-β drives the differentiation of fibroblasts into myofibroblasts, resulting in perivascular and parenchymal fibrosis, which further compromises tissue architecture and function (30, 31).

The combination of RT with molecular targeted therapies (TTs) represents a cornerstone of modern oncology, offering potent synergy for tumor control. However, this synergy can also amplify off-target toxicity in normal tissues. In the context of brain metastases, concurrent RT and BRAFi has been increasingly associated with an elevated risk of RN (29, 32).

The clinical evidence supporting this association, however, is unevenly distributed across cancer types. As summarized in Table 2, the most compelling data originate from studies in melanoma and glioblastoma, where the use of BRAFi is well-established. These studies consistently report a higher incidence and sometimes atypical presentation of RN following SRS or fractionated RT when combined with targeted agents. For instance, a illustrative case involved a patient with MAP2K1-mutant melanoma who developed RN nine months post-SRS while on trametinib and low-dose dabrafenib, which was subsequently managed with bevacizumab (33). This and other cases underscore the clinical reality of this interaction.

In stark contrast, direct clinical evidence specifically linking BRAFi to RN in NSCLC remains scarce. The limited number of studies, as cataloged in Table 2, highlights a significant knowledge gap. This paucity of data is particularly concerning given the unique pathophysiology of lung cancer brain metastases and the increasing adoption of these targeted therapies in the NSCLC setting. The mechanisms underlying this increased risk—potentially involving radiosensitization, vascular toxicity, inflammatory and tissue repair interference—are explored in the following section.

BRAFi, used particularly in BRAF-mutant melanoma and lung adenocarcinoma, may potentiate radiation-induced neurotoxicity through mechanisms that are not fully elucidated but likely involve exacerbation of oxidative stress and inflammatory responses (16, 32). BRAFi such as dabrafenib and MEK inhibitors such as trametinib target the MAPK/ERK signaling pathway, suppressing tumor proliferation. When combined with radiation, BRAFi may amplify additional toxicities by enhancing radiosensitivity through several mechanisms:

Clinical data, primarily from melanoma, confirm the heightened RN risk with BRAFi+RT combination. Key risk factors include: Treatment Timing: Concurrent or closely sequenced administration (within ~3 days) carries the highest risk (16). RT Modality and Dose: SRS, with its high dose per fraction, is associated with a greater risk of symptomatic RN compared to fractionated WBRT when combined with BRAFi, likely due to more intense focal vascular injury (43).

RN manifests clinically in distinct phases with characteristic symptoms and imaging features that evolve over time. In the acute phase, patients commonly present with symptoms such as headache, cognitive dysfunction, and neurological deficits, reflecting early inflammatory and edema processes in the brain tissue. These acute symptoms may be transient but are indicative of initial radiation-induced cellular and vascular stress. As the injury progresses to the delayed or late phase, more chronic manifestations emerge, including white matter abnormalities, brain atrophy, and persistent cognitive decline. These late effects correspond to irreversible structural damage such as demyelination, necrosis, and microvascular injury (44, 45).

Advanced neuroimaging techniques, such as magnetic resonance imaging (MRI), in which including conventional T2-weighted imaging and diffusion tensor imaging (DTI), reveals white matter changes, edema, and atrophic changes, play a pivotal role in the diagnosis and monitoring of RN. But, distinguishing RN from tumor progression is challenging, particularly in patients on targeted therapy, as both conditions present with contrast-enhancing lesions and perilesional edema on MRI. Advanced neuroimaging techniques, such as MR spectroscopy, perfusion MRI, and PET-CT, can improve diagnostic specificity by evaluating metabolic and vascular changes (46). Additionally, routine molecular profiling may help identify high-risk patients early, facilitating preemptive intervention.

The combination of clinical symptomatology and multimodal imaging enhances the accuracy of RN diagnosis, enabling differentiation from tumor progression and guiding therapeutic decisions. However, challenges remain in correlating imaging findings with clinical symptoms due to the complex pathophysiology and heterogeneous presentation of RN. Rodent models have provided insights into cellular and molecular mechanisms but do not fully replicate human clinical and radiological features, underscoring the need for further translational research to optimize diagnostic criteria and imaging biomarkers for RN. Given these complexities, multidisciplinary collaboration involving oncologists, radiation oncologists, and neurologists is essential for optimizing diagnosis and management.

In conclusion, the combination of BRAFi and RT for BRAF-mutant lung cancer brain metastases is a potent but double-edged sword, offering improved tumor control at the cost of increased RN risk. This review underscores the need for strategic BRAFi -RT integration, personalized dose adaptation, and vigilant monitoring. This interplay between RN and BRAFi effects necessitates a comprehensive understanding of molecular and cellular dynamics to inform clinical decision-making. Clinically, optimizing treatment regimens requires meticulous integration of molecular tumor profiling with advanced radiotherapeutic techniques. Tailoring the timing, dosage, and sequencing of targeted agents alongside precision radiotherapy modalities such as stereotactic radiosurgery or intensity-modulated radiotherapy can mitigate the risk of RN. Moreover, early pharmacologic interventions aimed at neuroprotection should be explored and incorporated into therapeutic protocols to safeguard neural tissue without compromising oncologic efficacy.

Looking forward, future research must prioritize elucidating the intricate molecular mechanisms underpinning RN, particularly the interactions between targeted therapies and radiation at the cellular and microenvironmental levels. Additionally, clinical trials evaluating innovative combination strategies that balance tumor control with neurotoxicity prevention are imperative. This review highlights the critical need for continued translational research and clinical innovation to achieve this balance and improve the prognosis for this challenging patient cohort.