MEK inhibitors for the treatment of extracranial arteriovenous malformations

Zi’an Xu, Jingwei Zhou, Yuxi Chen, Xi Yang, Chen Hua, Yunbo Jin, Xiaoxi Lin

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

Keywords:Arteriovenous malformation MEK1 MEKi Trametinib MAPK

A B S T R A C T

1.Introduction

Vascular malformations comprise a group of common challenging vascular disorders, primarily including infantile hemangiomas, venous malformations, arteriovenous malformations, port-wine stains, and lymphatic malformations.1with approximately 70 million affected individuals globally and an incidence rate as high as 1%.These conditions are listed among the 30 Current Problems in Surgery by the American College of Surgeons.

Arteriovenous malformations (AVMs) are high-flow congenital vascular anomalies that account for 1.5%–4.7% of all vascular malformations.2,3AVMs consist of dilated arteries and veins and lack normal capillary beds between the abnormal arteries and veins.AVMs are prone to rupture and hemorrhage and have a high mortality rate,making them the most dangerous vascular anomalies.The sites of predilection for AVMs include the head and neck,followed by the extremities,trunk,and viscera.AVMs can be localized with pain, ulceration, or recurrent bleeding and,in severe cases,can lead to heart failure due to prolonged hemodynamic abnormalities.4,5

AVMs are difficult to treat.Existing treatment modalities include interventional embolization and surgical resection.Both methods have advantages and disadvantages.Interventional embolization performed using conventional embolization agents cannot destroy vascular endothelial cells or remove AVM lesions.Disease progression after conventional embolization is reported in approximately 98% of patients.6,7In contrast,the absolute ethanol embolization agent can destroy vascular endothelial cells and have a complete effect, while mistaken embolization would cause serious complications such as necrosis of surrounding normal tissues, loss of vital organ function, and even death from cardiopulmonary failure.8,9Surgical resection is associated with a high risk of intraoperative hemorrhage and high progression rate of 81%.6Furthermore, AVMs can affect multiple organs, such as the extremities and the head.Surgery or interventional treatment is not recommended for large-area AVMs owing to the treatment efficiency and risk (Fig.1).Therefore, identifying safer and more effective treatment modalities is prioritized in clinical studies focusing on AVMs.

Although AVM is a congenital disorder, the underlying molecular mechanism remains unclear.Three molecular mechanisms have been demonstrated for familial and germline AVMs: AVMs in hereditary hemorrhagic hemangiectasia (HHT), AVMs in PTEN malformation-tumor syndrome, and AVMs in capillary malformation-arteriovenous malformations(CM-AVMs).The prevalence rate of HHT is approximately 1 in 5 000,and is caused by mutations in genes in the TGF-β signaling pathway.10,11The TGF-β signaling pathway plays a key role in HHT angiogenesis, and knockdown of TGF-β signaling pathway is caused by mutation of TGF-β signaling pathway.12,13The AVMs in PTEN hamartoma tumor syndrome(PHTS) and CM-AVMs are caused by mutations in PTEN and RASA1,respectively.14,15However, in addition to these three familial germline AVMs,a greater proportion of sporadic AVMs are caused by somatic mutations,which require further studies to identify the specific gene.

Fig.1.AVMs can affect multiple organs, such as the extremities and the head.

2.Research update of the MEK inhibitor in extracranial AVMs

Recent studies indicate that the candidate gene is most likely localized to mutations in the MAPK/ERK pathway(also known as the Ras-Raf-MEK-ERK pathway), including KRAS (e.g., p.G12D and p.G12V),MAP2K1 (e.g., p.F53L, p.Q56P, p.K57 N, p.Q58del, and p.D67Y), and BRAF (e.g., p.V600E).16–18MEK1 has an important role in mediating MAPK/ERK cascade signaling,and more than 35%of cancers have been associated with constitutively activating mutations of MEK1.19In 2017,Cuoto et al.identified 16 functionally acquired mutations with MEK1 in 25 extracranial AVM samples, and all endothelial cells in the samples were affected by MEK116indicating that the overactive Ras/MAPK pathway is one of the key factors in the formation of extracranial AVMs.Another study confirmed this finding,wherein variants in the Ras/MAPK pathway were reported in 36%of patients with AVMs.20The treatment of the transgenic zebrafish model of AVMs with the BRAF inhibitor vemurafenib improved the blood flow status of the lesions.

Based on these findings, mechanistic studies on MEK inhibitors for the treatment of AVMs are advancing.Several molecular, cellular, and animal studies have shown that MEK inhibitors inhibit the progression of extracranial AVMs.Overexpression of MAP2K1 altered the transcript abundance of more than 1 600 genes by inducing MAP2K1 expression in mouse endothelial cells (EC).21Among them, the highest upregulated transcript abundance was found in Col15a1 and Itgb3, suggesting that they may play a role in AVM formation.Another study used human AVM tissues carrying the MAP2K1 mutation and human umbilical vein endothelial cells(HUVECs)to study the pathway effects.This concluded that HUVECs carrying the MAP2K1 mutation showed considerable significantly more phosphorylated ERK1/2 than those of control HUVECs.22Moreover, the MEK inhibitor trametinib reduced ERK activation and vascular network formation,suggesting that MEK inhibitors could inhibit AVM formation and progression at the molecular level.

Furthermore,the findings of animal experiments support the idea that MEK inhibitors can inhibit AVM formation and progression.In one of these studies, knockdown of MEK1 in mouse embryos resulted in embryonic death due to abnormal angiogenesis and poor placental vascularization.MEK2 knockdown results in phenotypically normal mice.The finding further confirms that MEK1 plays an important role in the angiogenesis.23–25In addition, the administration of the MEK inhibitor trametinib in AVM mice with KRAS mutations in vascular EC was found to significantly increase the survival rate and reduce the size of malformed blood vessels in AVM mice.26

Similar findings have been reported for intracranial AVMs.A previous study found that active endothelial KRAS expression could lead to an altered vascular phenotype and the formation of brain arteriovenous malformations (bAVMs) in both mouse and zebrafish models.27In contrast, MEK inhibitors could reverse the established arteriovenous shunt in the zebrafish model.Another study demonstrated the role of KRAS gene mutations in promoting bAVM formation.28The formation of the bAVM was successfully induced by intracranial injection of adeno-associated virus(AAV)by mediating KRAS gene overexpression in mice.The growth of bAVM lesions was effectively inhibited after treatment with the MEK inhibitor trametinib.These results confirmed that KRAS mutations can promote the progression of bAVMs through the MEK/ERK pathway.These findings suggest that the Ras/MAPK pathway plays an important role in the development of bAVMs and that MEK inhibitors can inhibit the growth of bAVM lesions.Therefore, MEK inhibitors are potential therapeutic agents for the treatment of AVMs.

3.Application of the MEK inhibitors in extracranial AVMs

The MAPK pathway (RAS-RAF-MEK-ERK-MARP) is important for tumor proliferation.29Several marketed and investigational drugs targets the MAPK pathway.30Among them, MEK inhibitors affect the MAPK pathway through their action on MEK proteins, thereby inhibiting cell proliferation, which is similar to the mutation site of extracranial AVMs.31To date,of the 15 MEK inhibitors in active clinical development,4 of them (trametinib, binimetinib, selumetinib, pimasertib) have been approved by the FDA to treat melanoma, NSCLC, thyroid cancer, and neurofibroma.32These MEK1/2 inhibitors can be administered orally and are allosteric, selective, ATP-non-competitive, and difficult to cross-inhibit other targets.Few studies have investigated the molecular mechanisms of action and clinical treatment of extracranial nonfamilial AVMs with MEK inhibitors.

Trametinib (also known as GSK1120212) is an oral, reversible, and highly selective MEK1/2 inhibitor.Trametinib was approved by the FDA in 2013 for the treatment of unresectable or metastatic melanoma with the BRAF V600 E/K mutation.33Trametinib exhibited good inhibitory effects on tumors expressing MEK1 mutations.34–37

Two clinical cases demonstrated the potential efficacy of trametinib in treating AVMs.In 2018, Ramrada et al.reported the case of a child with a poor response to sirolimus.The child was found to harbor a MEK1 mutation after gene sequencing, and treatment with the MEK inhibitor trametinib was initiated.After 6 months of continuous treatment with trametinib (0.5 mg, BID), the lesion size reduced considerably, and magnetic resonance examination confirmed a substantial reduction in the volume and caliber of the vasculature.38The result suggested the preliminary efficacy of trametinib in MEK1-mutated AVMs.In 2021,Cooke et al.reported another case of KRAS-positive(KRAS is an upstream locus in the MAPK pathway) AVMs of the chest and spinal cord.The patient was continuously treated with trametinib for up to 2.5 years.Although the chest symptoms recurred during the treatment, magnetic resonance flow assessment demonstrated a considerable reduction in lesion blood flow rate(2.2 L/min prior to treatment,which decreased to 0.5 L/min after 6 months of treatment),and a reduction in lesion size.39Regarding safety concerns,the most common treatment-related toxicities of MEK inhibitors were diarrhea, fatigue, peripheral edema, cardiac toxicities (reduced ejection fraction and ventricular dysfunction), hematologic,and ocular complications.32

Although MEK inhibitors have shown good therapeutic efficacy against MEK-mutant AVMs, existing clinical studies are scarce.To date,only four clinical trials have been conducted globally: two are investigator-initiated and two are registry studies, as listed in Table 1.40–43

FCN-159 is an orally available and highly potent selective MEK1/2 inhibitor with a similar mechanism of action to mirdametinib and selumetinib.44FCN-159 is intended to be mainly used for the treatment of advanced solid tumors, type I neurofibromas, histiocytic tumors, and arteriovenous malformations.As the leader unit, our team, the Department of Plastic and Reconstructive Surgery of Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine,led the clinical trial of FCN-159 for the treatment of AVMs.

4.Conclusion

Surgical treatment challenges associated with AVMs are internationally recognized owing to their high risk of bleeding and recurrence rates.Although surgery and interventional embolization are available,efficient and safe treatments for large-area and complex AVMs are lacking, for which existing treatments are ineffective.Targeted therapy should be considered as a potential treatment for these patients.Recent findings on MAP2K1 mutations in AVM endothelial cells have opened a new direction.Several studies have confirmed that overactivation of theRas/MAPK pathway mediates the occurrence and development of AVMs.The use of selective MEK1/2 inhibitors, such as trametinib, in animal models can effectively inhibit AVM progression,improve blood flow,and achieve therapeutic effects.This suggests that MEK inhibitors may be considered a safe and effective therapeutic agent for AVMs and may also provide new ideas for the future treatment of vascular malformations.

Table 1 Ongoing clinical trials of MEK inhibitors for the treatment of AVMs.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All the authors have consented for the publication.

Authors’ contributions

Xu Z: Writing-Original draft.Zhou J: Visualization.Chen Y: Conceptualization, Methodology.Yang X: Writing-Review and editing.Hua C:Writing-Review and editing.Jin Y:Conceptualization,Methodology.Lin X: Supervision.

Declaration of competing interests

Lin X is an editorial board member for Chinese Journal of Plastic and Reconstructive Surgery and was not involved in the editorial review or the decision to publish this article.All authors declare that there are no competing interests.

Acknowledgments

This work was sponsored by 2023 Shanghai Jiao Tong University Medical-Industrial Intersection Key Project (grant no.YG2023ZD13):Screening of Novel Targeted Inhibitors Based on Genetic Vascular Malformation Organoid Models.