Background: Brain arteriovenous malformation (bAVM) is an abnormal vascular mass with disordered arteriovenous connection. Endothelial KRAS mutation is common in bAVM. In vivo studies have demonstrated that mutations of KRAS in somatic cells can induce bAVM-like angiogenesis, suggesting that KRAS gene may play a key role in the development and progression of bAVM. Summary: In this article, we will provide a comprehensive review of action mechanisms of KRAS mutations in the development of bAVM and summarize potential targeting drugs for KRAS mutations in bAVM somatic cells. Key Message: KRAS mutation in human brain endothelial cells is a key driver in the pathogenesis of sporadic cerebral arteriovenous malformations. It is of great clinical importance to explore and summarize the changes in the signaling pathway induced by KRAS mutation, which may provide additional targets for the treatment of sporadic bAVM development.

Brain arteriovenous malformation (bAVM) is a high-flow vascular lesion with direct artery-to-draining vein connection, lacking a capillary network [1]. It is the primary cause of spontaneous intracranial hemorrhage in pediatric and young patients [1]. Due to limited understanding of bAVM’s pathogenesis, current treatments are surgical resection, endovascular embolization, or stereotactic radiotherapy [1]. Conventional surgical treatment of bAVM is not fully curative and poses the risk of severe neurological deficits, especially when the lesion is located in functional areas or has specific vascular constructs. Thus, it is crucial to understand the molecular events driving bAVM development to develop precise and reliable targeted drugs for treating this potentially devastating cerebrovascular condition.

Previous studies have shown that both genetic and environmental factors may induce the formation and promote the progression of bAVM. A small proportion of bAVM cases are caused by familial vascular malformation syndrome resulting from known germline or inherited mutations. Over 95% of bAVM cases are sporadic, with no clear family history [1]. Studies in recent years have repeatedly demonstrated the widespread presence of KRAS somatic mutations in sporadic bAVM and its pivotal role in the progression of bAVM formation [2]. KRAS acts as a subfamily of RAS proteins that regulate cellular functions. The increased activity of downstream signaling pathways caused by its activating mutations has been shown to mediate the proliferation, invasion, and metastasis of a variety of malignant phenotypes [3]. Studying the impact of KRAS somatic mutations on the bAVM vascular microenvironment can provide valuable insights into the molecular mechanisms responsible for abnormal vascular construct formation and rupture in bAVM [3]. This understanding is crucial for developing targeted therapies and improving treatment strategies for affected patients.

In this review, we begin with a concise overview of KRAS-related signaling pathways. Subsequently, we delve into the role and mechanism of KRAS mutations in bAVM development. Finally, we compile information on potential drugs capable of targeting KRAS for bAVM, aiming to offer fresh insights for exploring bAVM’s pathological mechanisms and developing targeted medications.

KRAS Introduction

The RAS oncogene family comprises three members: Harvey (HRAS), neuroblastoma (NRAS), and Kirsten (KRAS) [4]. Although they share significant sequence homology, they play distinct roles in cellular signaling pathways and exhibit diverse tissue expression patterns. KRAS, located on chromosome 12 s short arm (12p11.1–12p12.1), was initially identified in lung cancer cells. Selective splicing of its fourth exon gives rise to two functionally similar protein isoforms: KRAS-4B (188 amino acids) and KRAS-4A (189 amino acids) [4]. Due to higher KRAS-4B mRNA levels, KRAS protein is commonly referred to as KRAS-4B.

The protein structure of RAS includes a G-structure domain and a high-surface region (HVR). RAS is an important signaling protein that displays GTP enzyme activity, enabling it to catalyze the hydrolysis of GTP into GDP (guanosine diphosphate) [5]. While in its GDP-bound state, RAS remains inactive. However, once it binds to GTP, it undergoes activation, and this activated form acts as either a monomer or a dimer to trigger downstream effector proteins, initiating crucial cellular signaling cascades. The functional activity of KRAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Stimulation by certain cytokines reduces KRAS affinity for GDP, replacing it with GTP, leading to RAS activation and downstream signaling. Conversely, GAPs enhance KRAS’s GTPase activity, promoting GDP binding and maintaining the resting state [6].

Signal Pathways Regulated by KRAS

KRAS proteins act as a molecular switch that finely regulates cellular phenotypes by regulating various signaling cascades. Upstream multiple stimuli, such as growth factors, chemokines, and Ca2+, can activate KRAS proteins [7]. Once activated, KRAS can mediate multiple signaling pathways involved in cell proliferation, migration, angiogenesis, and other phenotypes, highlighting its broad impact on cellular microenvironmental homeostasis [8].

Upstream Signals That Regulate KRAS

Receptor tyrosine kinase (RTK) is a key regulator in the upstream regulation of KRAS and can be activated by growth factors, hormones, and other extracellular signals to recruit bridging proteins, such as growth factor receptor binding protein 2 (GRB2), which in turn recruits SOS1 [9]. SOS1 catalyzes the replacement of GDP by GTP on KRAS, leading to its activation. In addition, RAS guanine nucleotide releasing factor 1 (RAS-GRF1) with its RAS exchange factor and calcium-binding EF-HAND domains, is another KRAS regulator, integrating intracellular signaling pathways to activate KRAS [7].

RAF-MEK-ERK Pathway

The RAF-MEK-ERK pathway is a classical downstream target of KRAS signaling. Activated KRAS recruits RAF to the plasma membrane, causing conformational changes in RAF and promoting its activation through homodimerization or heterodimerization with RAF family members [10]. Activated RAF then activates MEK, a bispecific protein kinase, which, in turn, phosphorylates ERK1 and ERK2 (extracellular signal-regulated kinase) [10]. Activated ERK translocates to the nucleus and activates various transcription factors that regulate the expression of genes involved in cell proliferation, differentiation, and survival, such as ELK1 and c-Fos [11]. Abnormal activation of the KRAS-RAF-MEK-ERK pathway has been linked to various cancers, including lung, colorectal, and pancreatic cancers [11]. Therefore, understanding the mechanisms that regulate KRAS signaling and the RAF-MEK-ERK pathway is important for the development of targeted therapies for cancer treatment.

PI3K-AKT-mTOR Pathway

The PI3K-AKT pathway is another downstream signaling pathway activated by KRAS. Dysregulation of the PI3K-AKT-mTOR pathway is significantly associated with various malignancies and vascular malformations [12]. Activated KRAS recruits and activates PI3K, which catalyzes the recruitment and activation of downstream AKT, a serine/threonine kinase that activates downstream targets such as mTORC1 and glycogen synthase kinase-3β (GSK3β), by the second messenger phosphoinositide triphosphate (PIP3) generated at the plasma membrane (PIP2) [12]. Activated mTORC1 promotes protein synthesis by activating downstream targets such as ribosomal protein S6 kinase (S6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1), while activated GSK3β regulates various cellular processes such as cell proliferation, differentiation and metabolism [12]. In addition, KRAS can activate the PI3K-AKT-mTOR pathway through other mechanisms, such as directly interacting with AKT or activating upstream receptors of the PI3K-AKT-mTOR pathway, such as the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor (IGFR) [13].

RalGDS Pathway

The RAL guanine nucleotide dissociation stimulator (RalGDS) pathway is activated by KRAS through direct interaction with RalGDS, which facilitates the release of GDP from RalA or RalB, thus acting as a guanine nucleotide exchange factor (GEF) to activate RalA or RalB GTPases [14].Activated RalGTP activates downstream effectors, such as PLD1 and components of the cytosolic complex, influencing cell proliferation, survival, migration, and vesicle transport [14]. KRAS mutations have been shown to activate RalGDS signaling and promote various cancers, including pancreatic, colorectal, and lung cancers [14].

TIAM1-RAC-Rho/PAK Pathway

KRAS is involved in the TIAM1-Rac-Rho/PAK pathway, crucial for cell activities (shape, migration, adhesion, actin cytoskeleton, endocytosis, and membrane trafficking). Activated KRAS interacts with TIAM1, a specific GEF, promoting RAC (Ras superfamily GTPase) activation. Once activated, RAC activates downstream effector molecules such as Rho and serine/threonine-protein kinase Pak, regulating cytoskeleton, cell migration, and division [15]. Studies have shown that KRAS mutations promote Rho and PAK activation and contribute to tumor cell invasion and metastasis [15]. In addition, inhibition of Rho signaling was found to reduce the proliferation and migration of KRAS mutant cells [16].

PLCε Pathway

The phospholipase Cε pathway is another downstream effector of KRAS signaling. Activated KRAS can promote PLCε activation by interacting with the Ras-binding structural domain of PLCε [17]. Activated PLCε activates membrane phosphatidylinositol 4,5-bisphosphate (PIP2), which in turn produces the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) [17]. IP3 binds to receptors on the endoplasmic reticulum, causing Ca2+ release into the cytoplasm. An increased Ca2+ concentration activates various Ca2+-dependent enzymes and transcription factors that play important roles in cell proliferation, differentiation, and apoptosis [7]. On the other hand, DAG activates various isoforms of protein kinase C (PKC) and downstream substrates after phosphorylation. PKC isoforms have multiple cellular functions, including regulation of cell proliferation, differentiation, and survival [17]. Dysregulation of this pathway is linked to various diseases, such as cancer, cardiovascular disease, and neurological disorders. Additionally, KRAS-PLCε activation not only promotes the proliferation and migration of vascular smooth muscle cells (VSMC) and endothelial cells (ECs) but also participates in the expression of genes related to inflammation and oxidative stress, which are key events in the progression of vascular diseases such as atherosclerosis and restenosis [17] (Fig. 1).

Fig. 1.

The regulation of KRAS activation and signal transduction. The canonical and well-known pattern of KRAS activation is dependent on correct membrane localization and activation of the adjacent membrane receptors. In the resting state, KRAS normally binds with GDP in an inactivated state. When the extracellular growth factors such as EGF transmit signals to receptors, the SOS, a kind of GEF, interacts with the KRAS-GDP complex, leading to the release of GDP and the replacement of GTP. The tether of GTP and KRAS induces structural changes of switch I and switch II, thereby activating KRAS. In contrast, GAPs enhance intrinsic GTPase activity in KRAS to accelerate the reaction, resulting in hydrolysis of GTP to GDP. The KRAS cycle between the activated and inactivated conformations functions as a finely regulated molecular switch that controls multiple signaling cascades, including the RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, and other signaling pathways, which are required for KRAS-dependent tumor growth and endocytosis and cytoskeletal organization.

Fig. 1.

The regulation of KRAS activation and signal transduction. The canonical and well-known pattern of KRAS activation is dependent on correct membrane localization and activation of the adjacent membrane receptors. In the resting state, KRAS normally binds with GDP in an inactivated state. When the extracellular growth factors such as EGF transmit signals to receptors, the SOS, a kind of GEF, interacts with the KRAS-GDP complex, leading to the release of GDP and the replacement of GTP. The tether of GTP and KRAS induces structural changes of switch I and switch II, thereby activating KRAS. In contrast, GAPs enhance intrinsic GTPase activity in KRAS to accelerate the reaction, resulting in hydrolysis of GTP to GDP. The KRAS cycle between the activated and inactivated conformations functions as a finely regulated molecular switch that controls multiple signaling cascades, including the RAF-MEK-ERK pathway, PI3K-AKT-mTOR pathway, and other signaling pathways, which are required for KRAS-dependent tumor growth and endocytosis and cytoskeletal organization.

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Other Signaling Pathways

KRAS regulates multiple signaling pathways with significant implications for various cellular processes. It activates the NF-κB pathway by promoting IκB degradation, allowing NF-κB translocation to the nucleus, and regulating gene transcription [18]. Additionally, KRAS activates the JAK-STAT pathway, leading to STAT activation and target gene regulation. In addition, KRAS can regulate the Hippo signaling pathway, activating YAP and TAZ by inhibiting their phosphorylation and degradation, leading to target gene expression [19]. Finally, KRAS is involved in regulating the Wnt signaling pathway. It interacts with and regulates β-catenin, a key component of the Wnt pathway, leading to the activation of downstream target genes [20]. All these pathways play key roles in embryonic development, tissue homeostasis, and tumorigenesis. In summary, KRAS plays a central role in a variety of signaling pathways that regulate various cellular processes.

AVM can occur in any part of the body, and AVM described in the current study usually refers to cutaneous soft tissue AVM, excluding internal organs such as the lung and gastrointestinal tract, with a few cases involving the cartilage or bone, especially the head and neck, accounting for 77.1%, followed by the extremities, accounting for 20.9% [21]. Al-Olabi et al. [22] conducted a study on 25 AVM patients to explore the potential genetic mechanisms of sporadic vascular malformations and found that one of these patients had a cerebral AVM. They also found chimeric mutations in the RAS/MAPK signaling pathway in 9 (36%) of the 25 patients, including four with KRAS mutations. Sissy et al. [23] reported a high mutation rate of pathogenic somatic variants in eAVM, mainly occurring in MAP2K1 and KRAS. Interestingly, the only patient with intracranial AVM in their cohort (in addition to eAVM) had a KRAS mutation, while the other 5 KRAS carriers did not have intracranial AVM [23].

KRAS Mutations Are Widespread in bAVM

Most brain AVMs are sporadic, without a clear family history. They may result from somatic mutations in the affected tissue, where a genetic mutation in a small cell fraction can trigger pathological development, as demonstrated in various diseases like cancer [24]. Somatic mutations are post-synthetic and create genetically distinct cells known as chimeras. Genetic chimeras are relatively common in the human body, as normal tissues, including the brain, inevitably accumulate mutations at any stage of life. Typically, these mutations do not significantly impact the phenotype or function of somatic cells. However, when mutations occur in key genes related to cell proliferation and death, somatic cells carrying these mutations may gain growth and proliferation advantages, leading to clonal expansion of mutant tissues and the development of diseases [25]. Therefore, somatic mutations could better explain bAVM features like sporadic occurrence, focal onset, and progressive spread of the pathology.

Advances in second-generation sequencing have enabled somatic mutation detection in malformed tissues, leading to a major breakthrough in understanding sporadic bAVM pathogenesis [24]. Since 2018, studies have demonstrated that activating mutations in the MAPK signaling pathway are significantly associated with vascular malformations. Targeted sequencing identified 24 potential bAVM-associated somatic mutations in 11 MAPK pathway genes. Among them, KRAS mutations are recurrent (G12V, G12D, and Q61H), suggesting their essential role in bAVM formation [26]. Further studies found varying frequencies of KRAS mutations in bAVM patients (2.13–52.15%) [26]. KRAS mutations were not present in all cells and occurred differently in each patient. Phenotypic heterogeneity in bAVM results from mutation differences, timing, tissue or cell type, and inter-crosstalk with other pathways. Genetic, environmental, and lifestyle differences also influence somatic mutation patterns, making the etiology unclear. Mutations may develop post-hapten during embryonic development due to DNA replication errors or local cellular stress causing irreversible DNA damage. Angiogenic signaling pathways are overactivated in cells with these mutations, central to abnormal vascular pattern development [3].

Impact of KRAS Mutations on bAVM ECs

ECs are one of the hotspots in bAVM research. In bAVM, ECs exhibit an immature and overactive phenotype and express higher levels of pro-angiogenic factors, and at the same time, the blood-brain barrier function is disrupted to varying degrees, leading to microhemorrhage and even rupture [27]. Upregulation of pro-inflammatory adhesion molecules (e.g., intercellular adhesion molecule-1) or cytokines (e.g., interleukin 8) in ECs mediates the infiltration of immune cells into the perivascular microenvironment [28]. VEGF plays an important role in the development of bAVM. Related studies suggest that VEGF mediates the angiogenic phenotype via RAS activation [29]. In vitro experiments with human umbilical vein ECs overexpressing KRASG12V showed significant upregulation of angiogenesis, cell cycle, and MAPK-related genes, along with increased EC permeability [30]. Nikolaev et al. [26] showed a significant correlation between KRAS mutation frequency and the percentage of ECs in bAVM tissues. They suggested that KRAS mutations in ECs are a key molecular event and a major feature in bAVM pathogenesis. A subsequent in vivo experiment [2] showed that KRAS-activating mutations in ECs induced abnormal AVM-like vessels in mouse and zebrafish models. Unlike other AVM mouse models (e.g., hereditary hemorrhagic capillary dilation), KRAS-mutant adult mice developed AVM without external injury or angiogenic stimulation, indicating KRAS in ECs independently contributes to the required vascular microenvironment for angiogenesis and remodeling. Subsequent studies revealed that KRAS activation enhanced EC migration and altered cell shape and actin dynamics without affecting EC proliferative capacity.

Phosphorylation levels of ERK1/2 significantly increased in KRAS-mutated ECs from bAVM samples, while AKT phosphorylation levels showed no significant differences. RAS-MAPK-ERK pathway inhibitors restored KRAS mutation-induced transcriptional profile changes in ECs, reversing AVM-like angiogenesis and arteriovenous shunt formation. Inhibiting the PI3K-AKT pathway did not cause corresponding changes [2]. These results suggest that KRAS-activating mutations in ECs may mediate the pathological phenotype of bAVM via RAS-MAPK-ERK pathway. However, in vivo and in vitro experiments with the KRASG12V mutation did not significantly induce EC proliferation, which contradicts previous studies showing active EC proliferation in bAVM. Further exploration is needed to understand the reasons and mechanisms behind this discrepancy [30].

Functional enrichment analysis of altered transcriptional profiles in KRASG12V-expressing ECs revealed significant enrichment of Notch pathway-related genes (e.g., NOTCH1, HES1, and HEY2). These genes are involved in angiogenesis, arteriovenous specification, and the pathogenesis of arteriovenous malformations [30]. Key genes in bAVM vascular remodeling (e.g., VEGFA, VEGFC, DUSP5, and HLX) were significantly induced in expression, pending validation at cellular and tissue levels. Additionally, endothelial-mesenchymal transition-related genes (e.g., SNAI1, SNAI2, ZEB1, and PCDH1) were significantly enriched. EndMT is widespread in bAVM, reported in several studies as a key factor mediating vascular remodeling and rupture bleeding [31]. Xu et al. [32] demonstrated that endothelial KRASG12D mutation mediated EndMT through MAPK-ERK activation. Their further study confirmed the downstream pathway as ERK-TGF-β/BMP-SMAD4.

Despite the low rate of KRAS mutations in bAVM ECs, EndMT is widespread in bAVM tissues, suggesting that low-frequency KRAS mutations may lead to widespread EndMT occurrence in bAVM ECs by perturbing EC-EC intercommunication [31]. He et al. [33] demonstrated that exosomal miR-3131 from KRASG12D mutant ECs promoted EndMT in neighboring KRAS wild-type ECs by targeting PICK1. These studies provide new insights for biomarker and mechanistic research in bAVM using cellular and animal models based on KRAS mutations.

Potential Impact of KRAS Mutation on Other Vascular Cells

In addition to ECs, other vascular components like VSMCs, pericytes, and astrocytes contribute to bAVM vascular remodeling and progression [34]. Pericytes play a crucial role in the capillary wall. Reduced perivascular cell coverage in human and mouse bAVM is linked to increased vessel permeability and higher bleeding risk [30]. The primary reason for this loss is reduced recruitment of mural cells during bAVM angiogenesis [34]. ECs and pericytes interact during bAVM formation, and ECs without pericyte protection fail to form the basement membrane, leading to increased tube diameter and abnormal morphology [34]. Sun et al. [30] found that KRASG12V expression in ECs reduced pericyte recruitment and vascular basement membrane formation, resulting in disrupted capillary formation and promoting AVM-like vascular remodeling (Fig. 2).

Fig. 2.

KRAS mutations are widely present in bAVMs. KRAS mutation in brain vascular ECs activates the RAS-MAPK-ERK pathway, which in turn stimulates arteriovenous differentiation and angiogenesis and activates TGF-β-SMAD4 pathway. Activation of TGF-β-SMAD4 pathway induces endothelial-mesenchymal transition, thus promoting the development and progression of bAVM. Crosstalk between mutant ECs and pericytes significantly promotes pericyte loss.

Fig. 2.

KRAS mutations are widely present in bAVMs. KRAS mutation in brain vascular ECs activates the RAS-MAPK-ERK pathway, which in turn stimulates arteriovenous differentiation and angiogenesis and activates TGF-β-SMAD4 pathway. Activation of TGF-β-SMAD4 pathway induces endothelial-mesenchymal transition, thus promoting the development and progression of bAVM. Crosstalk between mutant ECs and pericytes significantly promotes pericyte loss.

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Recently, a research team developed an in vitro microfluidic model of AVM on a microchip by seeding a mixture of wild-type ECs and KRAS4AG12V mutant ECs in a specific ratio. Their results showed that the vascular structure formed by the mutant KRAS4AG12V ECs exhibited a wider vascular bed and higher permeability compared to wild-type ECs alone. This model represents key structural and potential functional features of human AVM, suggesting that KRAS4AG12V may be sufficient for AVM formation in vitro and confirming the critical role of the RAS-MAPK pathway in pathogenesis. However, the model did not fully simulate the human cerebrovascular environment, as it lacked pericytes, smooth muscle cells, and astrocytes. Further improvements are needed before this microarray model can become a comprehensive research platform for observing bAVM development, cell phenotype, and therapeutic targets [35].

Fish et al. [2] established the first KRAS-associated transgenic bAVM mouse model using two approaches: (1) conditionally knocking the KRASG12D gene from a bAVM patient into mice, resulting in most newborn mice’s death and no bAVM development in survivors; (2) using CNS- and EC-specific Cre drivers to initiate KRASG12D expression in CNS ECs from birth, leading to almost 50% of the mice developing bAVM by 2 months of age. Cerebral AVM also occurred in adult mice with fully developed cerebrovascular systems, suggesting malformation formation is not solely dependent on physiological angiogenesis during development. Park et al. [36] innovatively used adenovirus-mediated specific overexpression of KRASG12V in ECs to induce the unique morphology of human bAVM foci in mice. These bAVM model-related studies provide a new preclinical mouse model for bAVM research, independent of induced germline mutant mice, and more representative of sporadic bAVM, aiding therapeutic strategy development for patients with bAVM.

How KRAS mutations affect the clinical presentation or natural history of bAVM is unclear. bAVM patients with KRAS mutations are more likely to present with bleeding at first presentation, and variant allele frequency is negatively correlated with the lesion volume and maximum diameter [37]. There was no significant difference in age at diagnosis, age at intracranial hemorrhage, gender and AVM location between patients with/without KRAS or BRAF mutations [37].

It was found in a bAVM mouse model constructed by targeting mutations in the KRASG12D locus that early expression of KRASG12D in ECs of embryonic mice resulted in cerebral hemorrhage and early death, whereas induction of KRASG12D mutation in ECs of adult mice did not result in lethal cerebral hemorrhage; rather, it also produced specific manifestations of bAVM [2]. Park et al. [38] demonstrated that virus-mediated overexpression of brain vascular endothelial-specific KRASG12V induced bAVM, established a clinically relevant bAVM mouse model, and showed multifocal hemorrhages on the surface of the dorsal/ventral OB or ventral MB regions of the brain of their KRASG12V/bEC mice, which were not detected in controls. This may be a spontaneous cerebral hemorrhage occurring in KRASG12V-induced bAVM. The manifestations shown in the above two mouse models of bAVM established by KRAS mutation showed that KRAS mutation may cause clinical manifestations of rupture hemorrhage in bAVM [36]. Sustained activation of the RAS pathway was found to lead to capillary dilation and diffuse intracerebral hemorrhage in HRAS-activated transgenic mice, but no bAVM occurred in HRAS-mutated transgenic mice, suggesting that different phenotypes of RAS proteins play distinct roles in angiogenesis and homeostasis [39].

Fu et al. [38] showed that EndMT was positively correlated with bAVM microhemorrhage and that SMAD6 was significantly downregulated during bAVM microhemorrhage and promoted EndMT in HUVECs through activation of the TGFβ/BMP signaling pathway. Xu et al. [32] reported that KRASG12D mutation induced EndMT by activating the ERK-TGF-β/BMPSMAD4 pathway, which may indicate a higher risk of bleeding in patients with bAVM caused by KRAS mutations.

In contrast to extracranial arteriovenous malformation, targeted treatment of bAVM may be challenging if the malformed tissue cannot be surgically removed for genetic analysis. In the absence of tissue samples, targeted drug therapy based on the most common KRAS somatic mutations in bAVM may be a viable solution.

Targets for treating KRAS mutation-induced diseases focus on downstream signaling molecules due to the specific structure of KRAS proteins, making it challenging to develop targeted drugs. Recent studies show MEK inhibitors can inhibit angiogenesis and Notch pathway activation in KRASG12V ECs [30]. Trametinib, a MEK/ERK inhibitor, attenuates KRASG12V-induced bAVM growth in mice [2]. Vemurafenib, a BRAF-targeted drug, restores abnormal vascular morphology in an AVM zebrafish model with RAS-MAPK pathway-related gene mutations [22]. Limited cases of AVM patients treated with trametinib showed efficacy with reduced lesion size and symptoms [22]. Targeting the KRAS-MAPK pathway holds promise for bAVM treatment, but more studies are needed to assess tolerability, adverse effects, and optimal treatment parameters.

Studies on KRAS somatic mutations in bAVM have been essential in understanding its pathogenesis and therapeutic targets. New animal models have aided in identifying molecular changes in bAVM more precisely. However, small rodent models have limitations for preclinical trials. Inducing KRAS mutations in large animals could help develop bAVM treatments. Investigating pharmacological treatments targeting KRAS-related pathways for reducing bleeding risk requires further exploration. Validation in animal models and human tissue, along with clinical trials, is needed. Enhanced understanding of KRAS genes will open new research avenues for effective bAVM therapeutics.

All authors declare no conflict of interest.

This research was supported by the 234 Discipline Peak Climbing Program of Changhai Hospital (2020YXK033); Project from Shanghai Science and Technology Commission (23Y11906700); Shanghai Shenkang Three-year Action Plan Major Clinical (SHDC2023CRT007) Research Project.

Miao Pang: literature collection, organization, writing, and revision of the paper; Guanghao Zhang: supervision and revision of the paper; Xin Ding: preparation of the draft; Chenghao Shang, Yuhang Zhang, Rundong Chen, Zhe Li, and Guoli Duan: guidance and supportive contributions; and Qiang Li: critical review of the intellectual content of the article and financial support.

Additional Information

Miao Pang and Guanghao Zhang contributed equally to this work and should be considered first authors.

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