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Tyrosine kinase inhibitors in Ewing’s sarcoma: a systematic review

BMC Cancer volume 25, Article number: 735 (2025) Cite this article

Abstract

Ewing’s sarcoma (ES) is a highly aggressive primary bone malignancy that primarily affects children and adolescents. Several tyrosine kinase receptors (RTKs) have been found to be overexpressed in ES samples, and it was demonstrated that some play significant roles in driving the malignant phenotype of ES. Specifically, ES with insulin-like growth factor 1 (IGF1R) or vascular endothelial growth factor (VEGFR) overexpression were correlated with more aggressive ES and worse outcomes. Other RTKs that were determined to be overexpressed in ES include platelet-derived growth factor receptor, stem cell factor receptor, and hepatocyte growth factor. Overexpression of these molecules suggests their possible tumor-driving role, making them potential targets for intervention. Various tyrosine kinase inhibitors (TKIs), including apatinib, anlotinib, and cabozantinib have shown clinical promise in patients with recurrent ES who have progressed on previous lines of therapy. The findings reported in this review emphasize the importance of assessing IGF1R-focused inhibitors and combinational therapeutic regimens in future research. Furthermore, biomarkers predictive of response are necessary to improve patient outcomes. In order to optimize ES care, considerations for patient eligibility on the basis of positivity for biomarkers predictive of response, and the inclusion of quality-of-life evaluations in studies must be addressed.

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Introduction

Ewing’s sarcoma (ES) is a highly aggressive primary bone cancer that often occurs in the pelvic, femoral, and tibial bones. ES can also occur in soft tissues, such as the chest wall, gluteal muscle, and pleural cavities [1]. It predominantly affects children and adolescents, occurring annually in 2.93 cases per 1,000,000 [2]. It is the third most common primary malignant bone tumor, after osteosarcoma and osteochondroma, accounting for 6% of all bone tumors [3]. Ewing’s sarcoma lesions are characterized histologically by small round cells, similarly to primary neuroectodermal tumors. ES cells contain nuclei that occupy much of the eosinophilic cytoplasm [4]. Contrary to osteosarcoma [5] and chondrosarcoma [6], ES cells do not produce matrix [4].

Most ES samples exhibit the t(11;22) (q24;q12) chromosomal translocation, which combines the Ewing sarcoma breakpoint region (EWSR1) to the Friend leukemia integration (FLI) gene, resulting in the chimeric EWS/FLI transcription factor [7]. By binding to and interacting with other proteins, EWS/FLI roots the aggressive multiplication and malignant behavior of ES cells and endows them with stem-cell like properties. However, ES and other Ewing’s Family Tumors (EFTs) are more diverse than only tumors with the traditional EWSR1-FLI1 translocation. Other fusions between EWSR1 or translocated in liposarcoma/fused in sarcoma (TLS/FUS), a similar protein and other members of the ETS (E26 transformation-specific) family, such as erythroblast transformation-specific-related gene (ERG), E twenty-six variant transcription factor 4 (ETV4) and fetal hematopoiesis regulator (FEV) are known to occur in rare cases of EFTs [8].

The advancement of standard ES treatment, which now includes surgery, chemotherapy, and radiotherapy, has resulted in an increase in 5-year survival to 70% in patients with local lesions. However, only about a quarter of patients with relapsed or metastatic ES survive for more than 5 years [9], with treatment representing a substantial financial burden on patients [10]. Targeted therapies are increasingly used as therapies that bind to targets more specific to tumor cells, making them more selective than chemotherapy [11]. One of the most prominent targets for selective inhibition are tyrosine kinase receptors (RTKs), which hold various roles, including cell growth and proliferation. Tyrosine kinase inhibitors (TKIs) are a class of targeted drugs that specifically bind tyrosine kinase receptors and obstruct ligand binding, inhibiting downstream pathway activation [12, 13].

The goal of this study is to review evidence of tyrosine kinase gene mutation and protein expression in ES and detail the efficacy and safety of all tyrosine kinase inhibitors that were assessed in trials and retrospective studies in the treatment of ES.

Methods

A comprehensive search of the literature was conducted using the PubMed, Cochrane, and Google scholar (Pages 1–20) databases until November 2023. Using Boolean Operators, the MeSH term “sarcoma”, with the keywords “Ewing’s Sarcoma”, and “VEGFR”, or “PDGFR”, “KIT”, “c-MET”, ”IGF1R”, “regorafenib”, “anlotinib”, “cabozantinib”, “sorafenib”, “apatinib”, “pazopanib”, “imatinib”, “cediranib”, and “axitinib“ were applied after an extensive familiarization with the current literature was undertaken to discover the tyrosine kinase receptors and inhibitors pertinent to Ewing’s sarcoma. Information from other publications was added to provide context.

In total, 308 publications were retrieved. After titles and abstracts of extracted papers were reviewed for eligibility, whole texts were evaluated. The goal of this analysis is to review articles that contain data on the genetic mutations and protein expression of the most relevant RTKs in ES patient samples, as well as clinical studies, including trials and retrospective studies assessing the efficacy and safety of kinase inhibitors targeting these RTKs. Articles that focus on ES without data on tyrosine kinase gene mutation, protein expression, or association of any of the latter with ES were not included in our review. In vitro and in vivo studies, as well as reviews dating from before 2020, were also excluded from our analysis. Overall, 46 eligible articles were included in this review. The PRISMA diagram shown in Fig. 1 summarizes the process. These 46 references were specifically used in the sections detailing the expression and mutations of each individual RTK, as well as in the subsection dedicated to the efficacy and safety of each TKI. Additional references aimed to provide context, and were found through manual searches of relevant literature, including key citations from the retrieved papers.

Fig. 1
figure 1

PRISMA flowchart depicting the data curation process

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Results

Main pathways downstream of receptor tyrosine kinase inhibitors

The primary signaling pathways activated by RTKs encompass Mitogen activated protein kinase (MAPK), Phosphatidylinositol 3-kinase (PI3K), and Src family proteins [14]. In the MAP kinase signaling pathway, the activation of RTK leads to the phosphorylation MAPK1 and MAPK2, through multiple stages. MAPK1/2, upon activation, regulate the expression of genes associated with various cellular functions such as differentiation, invasion, and survival [15, 16].

Additionally, upon RTK activation, Phosphatidylinositol 3-kinase (PI3K) is recruited, leading to the phosphorylation of protein kinase B (Akt). Akt governs several cellular processes, including the activation of mammalian target of rapamycin (mTOR), cell survival, proliferation, and the promotion of blood vessel development [17]. RTKs also serve as upstream regulators in the activation of Src [18]. Src activation involves a recruitment mechanism [19] and necessitates the involvement of rat sarcoma (Ras) and Ras-like guanosine triphosphatases (GTPases) [20].

Fig. 2
figure 2

Representation of receptors tyrosine kinase involved in Ewing’s sarcoma and their mechanisms of action done via Biorender

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Key tyrosine kinase receptors in Ewing’s sarcoma (Fig. 2)

Information was used from 22 of the studies we have extracted to write the following part of the review. Other publications were cited to provide context.

Insulin-like growth factor 1 receptor (IGF1R)

The insulin-like growth factor 1 receptor (IGF1R) plays a role in promoting cell division, mobility, and invasion. Additionally, there’s an established association between IGF1R and the metastatic progression of cancer [21].

Insulin-like growth factor 1 (IGF1) levels were significantly increased in ES patients compared to controls (p < 0.0001) [22]. A study evaluating signaling pathways in ES demonstrated via IHC that IGF1R was expressed in 76.1% of samples [23]. High-grade ES tumors were also demonstrated to express higher levels of insulin-like growth factor binding protein 3 (IGFBP3) than low-grade ES. It was also found that IGFBP3 expression is correlated with IGF1 and IGF1R expression [22]. Moreover, the IGF1 to IGFPB3 ratio may be a prognostic factor indicative of survival [24]. IGF1R was also detected in approximately 57% of ES patients in a study assessing biomarkers in Ewing’s family of tumors [25]. In a different analysis, it was shown that IGF1R was expressed in all specimens sampled from 16 patients, with 60–100% of malignant cells harboring IGF1R. It was also shown that 25% of Ewing’s sarcomas showed high IGF1R expression. The subset of patients with high IGF1R expression had a somber prognosis (p = 0.0048) and shorter overall survival (OS) (p = 0.0398). Ewing’s sarcomas with high IGF1R expression tended to be more advanced, albeit this trend was not statistically significant (p = 0.0534) [26]. Treatment with IGF1R specific antibodies allowed patients to achieve better progression-free survival (PFS) and overall survival (OS), and patients with nuclear IGF1R responded better, indicating that IGF1R may be useful as a biomarker predictive of response to IGF1R targeting [27]. IGF1R expression was correlated with increased proliferative potential measured by the degree of Kiel 67 (Ki67) antibody binding [28], and was more expressed in metastatic (p < 0.05) and relapsed (P < 0.001) Ewing’s sarcomas, compared to local and non-recurrent tumors [22]. The role of IGF1R in ES is underscored by the more favorable outcomes of ES patients with increased ATP binding cassette subfamily A member 6 (ABCA6) expression, which is generally weakened in ES. This result can be explained by the fact that high expression of ABCA6 inhibits IGF1R and the pathway downstream of it [29]. Additionally, Epidermal growth factor receptor substrate 15 (EPS15) Homology Domain containing 1 (EHD1), which upregulates IGF1R expression and contributes to carcinogenesis and the metastatic potential of ES, was found to be overexpressed in 88.6% of a pool of 307 ES samples [30].

Vascular endothelial growth factor receptor (VEGFR)

VEGFR promotes the creation and expansion of blood vessels, breaking down the extracellular matrix, increasing vascular permeability, and attracting endothelial cells. Angiogenesis is a key aspect of tumorigenesis, playing a significant role in tumor growth and enabling metastatic dissemination [31].

In a study assessing potential prognostic factors for Ewing’s Sarcoma, it was revealed that vascular endothelial growth factor (VEGF) was overexpressed in 55–60% of tumors [32]. Another study assessing Ewing’s sarcoma family of tumors has shown that VEGF was overexpressed in 60% of samples, and that VEGF was correlated with microvessel density [33]. VEGF was determined to be a significant prognostic factor in ES and correlated with poor outcome (P = 0.0047) [32] and microvessel density (p = 0.02) [33]. It was also reported that Ewing sarcoma-erythroblast transformation specific (EWS-ETS) interacts with the VEGF promoter [32]. VEGFC was also overexpressed in pediatric ES [34]. When compared to controls, VEGFR2 was shown to be strongly (57%) or moderately (43%) expressed in tumor cells and endothelial cells sampled from human ES biopsies [35]. VEGFR1 was expressed in 12.5% of samples and was associated to substantially increased microvessel density (p = 0.0054) and age (p = 0.026). The expression of VEGFR2 was determined to be 8.2 arbitrary units, compared to 1.5 arbitrary units for VEGFR1. Furthermore, VEGFR2 expression was significantly correlated with lesion volume (p = 0.041) [36].

Epidermal growth factor receptor (EGFR)

Epidermal growth factor receptor (EGFR) is a part of the human epidermal growth factor receptor (HER) family, a group of RTKs, crucial in regulating cellular functions such as proliferation, survival, and migration [37].

In a study assessing signaling proteins in 40 patients, it was revealed using immunohistochemistry (IHC) that EGFR was expressed in 78.3% of ES samples [23]. Another study using labeled streptavidin-biotin complex (LSAB) IHC determined that 43% of ES patients showed HER2 expression, with 40% of those showing a high level of expression [25]. In a different analysis that included 113 ES patients, 16% of patients exhibited HER2 overexpression [38]. However, other studies have demonstrated that HER2 was not overexpressed in ES [32, 39, 40] and was not associated to any clinical outcome [38]. Overall, HER2 does not appear to be an important target in ES treatment [40]. HER4 expression, on the other hand, was found to be statistically correlated with decreased event-free survival in Ewing’s family of tumors specimens (p < 0.05), and higher HER4 expression was linked to metastatic disease (p < 0.05) [41].

Stem-cell factor receptor (KIT)

The stem-cell factor receptor (KIT) manages gene expression, cell survival, cell proliferation, and contributes to the processes of carcinogenesis, tumor expansion, and metastasis [42].

The KIT gene was mutated in 2.6% of patients in a multicenter study assessing KIT and PDGFR mutations [43]. Similar results were echoed by another analysis [44]. KIT was expressed in approximately 87% of patients with typical ES, with almost 63% of ES patients showing high expression, and 63% expressing stem-cell factor (SCF), the ligand of KIT. Only one patient with KIT expression was not positive to SCF staining, while SCF expression in two others was not verified [25]. In a different study, all Ewing’s sarcoma family of tumors samples exhibited KIT and SCF expression [44]. Similarly, 71% of ES and primitive neuroectodermal tumor stained positively for KIT [45]. However, in a study assessing KIT protein expression, it was revealed that only 27 out of 71 patients stained positively for KIT, and it could not be confirmed that activating mutations in the KIT gene were consistent with protein expression [43].

Platelet-derived growth factor receptor (PDGFR)

Platelet-derived growth factor receptor (PDGFR) holds diverse functions, including wound healing, embryonic development, and multiple functions within the central nervous system [46,47,48].

It was shown in a study studying the validity of imatinib in the treatment of ES that no activating mutations were found in specimens sampled from 71 patients [43]. An analysis assessing histological characteristics of Ewing’s sarcoma family of tumors showed that platelet-derived growth factor A (PDGFA) and PDGFB were overexpressed in 64 and 46% of samples, respectively [33]. Moreover, a study of the activation of various RTKs in Ewing’s family of tumors also revealed that no activating mutations of the PDGFR family of proteins were identified via polymerase chain reaction (PCR). However, PDGFRα and PDGFRβ were expressed and activated in all samples, with PDGFRβ showing high levels of expression and activity. PDGFA and PDGFB were also expressed in this set of samples. Anti-PDGFRα, anti-PDGFRβ was revealed via IHC in 100% and 52% of samples, respectively [44].

Hepatocyte growth factor receptor (HGFR)

The pathways activated by HGFR (hepatocyte growth factor receptor) or c-MET (mesenchymal-epithelial transition factor) play critical roles in governing various cellular functions such as cell movement, cell invasion, cell proliferation, and resistance to cell death. Additionally, HGFR contributes to the development and spread of metastasis [49].

The HGFR gene was mutated in 9% of lesions in a study that included 31 ES patients. The HGFR protein was detected in all samples, with at least 70% of malignant cells expressing the receptor. Furthermore, 30%, 56%, and 14% of samples exhibited high, medium, and low expression, respectively. It was also demonstrated that membranous expression of HGFR was associated to decreased overall survival (p = 0.014) [50].

TKIs assessed in ES treatment (Table 1)

Information was used from 24 of the references we have retreived to write the following part of this review. Other publications were used to provide context.

Table 1 Summary of the findings of the studies assessing the efficacy and safety of TKIs in ewing sarcoma
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Multi-tyrosine kinase inhibitors

Apatinib

Apatinib, also known as YN968D1, is an orally administered TKI that targets mainly VEGFR2, but that also inhibits Ret (rearranged during transfection), KIT and c-src receptors [51].

A retrospective study aiming to describe the use, efficacy, and safety of using apatinib as a treatment for patients with advanced sarcomas. Concerning the ES patients included in the analysis, more than half were treated with a combination of apatinib and everolimus, whereas the remaining patients were treated with apatinib alone. The best response recorded was a partial response. The median PFS was 2.0 months, while the overall response rate (ORR) and 12-week PFS were 70% and 22.5% respectively. The median duration of response was 2 months. The treatment was interrupted in 18% of the study’s cases and the toxicity profile appeared to be more severe than what was reported in previous studies, with 46.5% of patients having grade 3 or 4 adverse events (AEs) [52]. A retrospective study was conducted to investigate the efficacy and safety of apatinib in ES patients. The ORR was reported at 40% with partial response being the best response, while 40% of patients achieved stable disease and 20% had progressive disease. The median progression-free survival was 16 months, while the 6- and 12-month PFS rates were 81.8% and 71.6% respectively. A disease control rate of 80% was reported. Most of the adverse events were mild and manageable therefore the toxicity profile was deemed acceptable. Nonetheless, prospective studies with a larger number of patients and an extended follow-up are necessary to fully ascertain the clinical efficacy of apatinib in treating ES [53].

Anlotinib

Anlotinib is an oral TKI that inhibits VEGFR, PDGFRα/β, KIT and FGFR1 [54, 55]. Anlotinib was relatively successful in the treatment of ES, as patients had an ORR of 37.5%, and 50% of patients were progression-free at 6 months, the treatment was also well tolerated [56]. In a trial assessing Anlotinib, vincristine and irinotecan multi-drug therapy, patients achieved even better results, with 33.3% of pediatric patients achieving complete responses, and 55.5% of patients achieving partial responses, while producing tolerable toxicities. Most of the patients (92%) had at least a grade 1 AE, with 7 grade 3 or 4 AEs being reported [56]. In the same trial, it was determined that combination of Anlotinib, vincristine and irinotecan did not negatively affect the quality of life of ES patients [57].

Cabozantinib

Cabozantinib, or XL184, is an orally administered MTKI that targets VEGFR2, HGFR, RET, and KIT [58]. A phase I clinical study aiming to assess the maximum tolerated dose, pharmacokinetics, pharmacodynamics, efficacy, and safety of cabozantinib in treating children with refractory or relapsed solid tumors. Only one ES patient had prolonged stable disease. The toxicities caused by the drug were deemed manageable [59]. A phase II study evaluated the activity and safety of cabozantinib in patients with advanced ES and osteosarcoma. ES patients achieved an ORR of 25.6% within 6 months. The reported stable disease and progressive disease were 48.7% and 20.5% respectively. Median PFS was 4.4 months and median OS was 10.2 months. The 6-month PFS was 33.3%, whereas the 12-month OS rate was 48.8%. At least one serious AE was reported in 67.8% of patients, but overall, the treatment was well tolerated and demonstrated efficacy in treating ES. Italiano et al. analyzed the potential of vascular endothelial growth factor A (VEGFA), soluble VEGFR2 (sVEGFR2), hepatocyte growth factor (HGF), and soluble HGFR (sHGFR) as predictive biomarkers in Ewing sarcoma; however, none showed a significant association with outcomes or response to cabozantinib [60]. A retrospective study was conducted to analyze cabozantinib in the treatment adult patients with advanced osteosarcoma and Ewing’s sarcoma/primitive neuroectodermal tumors (PNET). In the Ewing’s sarcoma/PNET subgroup, 3 patients had stable disease as best response and an unspecified number of patients had progressive disease. Also, in this same subgroup of patients, median-PFS and median OS were 5.7 and 8 months while the 3 and 6-months PFS rates were 80% and 40% respectively. The study demonstrated that cabozantinib has a clinical efficacy in the treatment of advanced Ewing sarcoma, and the drug was deemed safe [61]. Another study was conducted to assess the use of regorafenib and cabozantinib treating in recurrent/refractory bone tumors including ES. Regarding ES patients treated with cabozantinib, authors reported an ORR of 25%. Median-PFS was 3.4 months and clinical benefit rate was 43.8%. The study found that cabozantinib showed significant real-world activity in treating ES [62].

Regorafenib

Regorafenib, or BAY 73-4506, is an orally administered TKI that targets mainly VEGFR1, VEGFR2, and VEGFR3 as well as RET, FGFR1, PDGFRβ and KIT [63]. In a phase II trial that assessed the efficacy and safety of regorafenib in the treatment of ES patients, the subset of patients that received regorafenib had a PFS of 11.4 weeks, compared to 3.9 weeks for patients who were given placebo, with 56% of the patients who received regorafenib experiencing serious AEs [64], with a different study providing similar results [62]. In another study assessing regorafenib in Ewing’s family of tumors, it was reported that patients achieved a PFS of 14.8 weeks, an objective response rate of 11% and an OS of 53 weeks, also the toxicity profile was acceptable [65]. Regorafenib, vincristine and irinotecan tritherapy was evaluated in a study that included patients with childhood cancers, five of whom had ES. Two of the ES patients achieved partial response, while the remaining ES patients had stable disease, the treatment was also well tolerated [66]. Overall, regorafenib showed some efficacy as a single-agent, and the use of regorafenib as part of a multi-drug treatment may further improve patient outcomes.

Pazopanib

Pazopanib, or GW786034, is a selective TKI that inhibits VEGFR-1, VEGFR-2, VEGFR-3, PDGFRα, PDGFRβ and KIT [67]. In a retrospective study, pazopanib was used as a treatment for patients with advanced soft tissue and bone sarcoma. Among the 3 ES patients included in the study, 2 patients had stable disease for 12 and 13 months respectively, whereas the third one had progressive disease. However, the observation of a durable stable disease in patients with ES, osteosarcoma and chondrosarcoma that were included in this study, showed that pazopanib has a significant efficacy in treating bone sarcomas [68].

Sorafenib

Sorafenib, or BAY 43-9006, is an orally administered TKI that targets VEGFR 2, VEGFR 3, PDGFβ, Flt-3 (Feline McDonough Sarcoma like tyrosine kinase 3), KIT, and RET. It also inhibits the RAF/MEK/ERK pathway [69, 70]. A retrospective study assessing the efficacy and safety of sorafenib in the treatment of patients with refractory bone tumors included two ES patients. One of them had progressive disease while the other had a partial response as best response. Both showed no grade 2 or 3 toxicities, but in the rest of the study 25% of patients had grade 3 skin toxicities. The overall response rate for the whole group was 75% whereas the 5-year overall survival estimate was 64.5% for the whole group [71]. In another analysis, a combination of bevacizumab, sorafenib and cyclophosphamide was given to patients with recurrent or refractory bone sarcomas. Of the 14 ES patients of this study, 11 achieved stable disease or better as best response, including one patient who achieved complete response and another who achieved partial response. Grade 3 or more AEs were reported in 94.8% of patients. The study found that this multidrug therapy showed clinical promise in treating bone sarcomas either as a maintenance protocol at the beginning of treatment or as a palliative treatment [72].

Axitinib

Axitinib, or AG-013736, is an orally administered TKI inhibitor with a potent activity against VEGF receptors 1,2 and 3 [73]. A phase I trial was conducted to assess the efficacy and safety of axitinib in the treatment of children and adolescents with recurrent or refractory solid tumors. Among the ES patients of this study, only one had stable disease for more than 6 cycles as best response However, no other findings specific to ES were provided. Regarding toxicities, 18.75% of patients had grade 3 toxicities, whereas no grade 4 toxicities were reported [74]. To assess the efficacy and safety of axitinib in ES patients, future clinical trials with larger ES cohorts are needed.

Cediranib

Cediranib, or AZD2171, is a highly potent and selective TKI inhibitor that targets mainly VEGFR2, VEGFR3 and VEGFR1 [75]. A phase I trial was conducted to evaluate the safety and efficacy of cediranib in the treatment of children and adolescents with refractory solid tumors. Among the ES patients included in the study, one patient with pulmonary metastasis showed partial response (77% reduction in tumor size), but the response was complicated by bilateral asymptomatic pneumothoraxes. No other findings specific to ES patients were stated. Further clinical trials shedding light on the efficacy and safety of cediranib in the treatment of ES patients are needed [76].

Lenvatinib

Lenvatinib is a TKI that inhibits VEGFR 1,2 and 3, FGFR1,2,3 and 4, PDGFRα, KIT and RET [77].

A phase I/II study aimed to assess the efficacy and safety of the combination of Lenvatinib and Everolimus to treat pediatric patients with solid tumors including Ewing sarcoma. All patients had AEs, among which 47.1% had grade 3 or 4 AEs [78].

Selective tyrosine kinase inhibitors

Gefitinib

Gefitinib, or ZD1839, is an orally administered TKI that inhibits the EGFR [79]. Gefitinib was assessed in the treatment of childhood cancers in multiple clinical trials. However, most included only a single or very few ES patients. Both trials with one ES patient reported a partial response [80, 81], while one of three Ewing’s family of tumors cases in a third trial was reported to achieve partial response [82]. The treatment was well tolerated in the 3 studies, with 31% of patients having grades 3 or 4 dose-limiting toxicities in the last one. Overall, the evidence of the efficacy of gefitinib in ES remains scarce, and more studies assessing this drug must be conducted to assess clinical benefit provided by gefitinib in ES.

Imatinib

Imatinib, or STI-571, is a TKI that inhibits KIT and PDGFR [83, 84]. A phase II study was conducted to evaluate the efficacy and safety of imatinib in treating children with refractory or relapsed solid tumors. Among all the ES patients included in the study, only one partial response was recorded. The study found that Imatinib does not appear to be a suitable treatment for treating recurrent ES [85]. In a phase II multicenter trial, none of the ES patients included in the study showed a clinical benefit response, while 13 patients showed progressive disease. Median PFS was 1.68 months, and no objective response was observed [86]. In a phase II clinical trial aiming to assess the efficacy of imatinib in the treatment of patients with recurrent EFTs or desmoplastic small round cell tumors expressing KIT and/or PDGFRα, the only patient to show a partial response was the one in whom the most elevated levels of PDGFRα and KIT expression were reported. This patient underwent 8 months of successful treatment. This finding could offer a basis for further development and research on TKIs as a therapy for patients with recurrent EFTs. The median OS and median PFS were reported at 6 months and 1 month respectively. Grade 3 AEs were reported in 28.5% of patients, whereas 14.28% of patients had grade 4 AEs [87].

Discussion (Table 2: upcoming trials assessing TKIs in Ewing’s sarcoma)

Ewing’s sarcoma is a rare, fast-growing primary bone cancer that predominantly occurs in adolescents and children. Patients with recurrent or metastatic ES frequently have a somber prognosis. The purpose of this study was to provide evidence of the validity of RTKs as appropriate targets in ES, and to analyze the clinical performance of TKIs in the treatment of ES. Some inhibitors such as cabozantinib, anlotinib, regorafenib, and apatinib showed clinical promise and further trials with larger cohorts are needed to fully evaluate the efficacy of these TKIs in treating ES. Several trials were performed to study the efficacy and safety of monoclonal antibodies in ES. Despite initial hopes, it was determined that IGF1R-specific monoclonal antibodies such modest benefits, with teprotumumab producing a 10% ORR in 115 patients with EFT [88]. Only 6% of patients with EFTs achieved an objective response in a trial assessing ganitumab [89]. Furthermore, only 2 of 16 patients with ES achieved an objective response in a trial investigating the efficacy and safety of figitumumab [90]. It can be concluded that TKIs are generally more effective than monoclonal antibodies in ES and other related tumors. This observation may be explained by the fact that small molecule inhibitors exert their effects intracellularly and extracellularly, and generally have a broader spectrum of inhibition, which is useful in tackling the substantial tumor heterogeneity found in bone sarcomas [91]. Other drugs, however, such as imatinib provided little to no efficacy in treating these tumors. Axitinib and cediranib were not assessed in studies with enough ES patients to draw conclusions regarding their efficacy or safety profile in the treatment of this histology of bone tumors.

Table 2 Upcoming trials assessing tyrosine kinase inhibitors in the treatment of ewing sarcoma and other tumors
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Combining TKIs with other drugs has shown clinical promise. The effectiveness of TKIs in treating ES is being evaluated in a number of current clinical trials, which are expected to conclude in the upcoming years. New therapy approaches for relapsed and refractory patients are the focus of studies like NCT05182164 (pembrolizumab + cabozantinib, completion: 2025), NCT05395741 (regorafenib, completion: 2025), and NCT06156410 (cabozantinib + ifosfamide, completion: 2028). These trials will produce critical information on efficacy and safety of TKIs in ES, possibly improving treatment techniques and discovering biomarkers predictive of response to TKIs. Their findings might influence treatment recommendations in the future and enhance patient outcomes. Researchers provided clinical data supporting the adding of statins to TKI therapy [29], and using anti-IGF1R and EHD1 combined therapy [29]. Future studies must also aim to assess combining TKIs with other modalities of treatment, such as chemotherapy, other targeted therapies, and immunotherapy. Doing so would almost certainly lead to increased response rates and survival times.

TKIs that specifically inhibit certain receptors often trigger toxicities associated with their mode of action. For example, TKIs that target VEGFR2, such as apatinib and anlotinib, disrupt angiogenesis, resulting in dysfunction in endothelial cells and microvascular injury that causes hypertension, wound healing deficits, rash, proteinuria, and hand-foot syndrome [52, 56], as well as hypertriglyceridemia and hypercholesterolemia in patients treated with anlotinib [56]. Shen et al., 2018). Clinical studies have reported a moderate overall rate of adverse events with VEGFR-targeting TKIs, with grade 3 or higher toxicities occurring in 4 to 14% of patients, highlighting their satisfactory safety burden [52, 56].

On the other hand, cabozantinib, a HGFR and VEGFR2 inhibitor, produced grade 3 and 4 toxicities in 68% of patients from the CABONE study, which included hypophosphatemia, rash gastrointestinal symptoms, increases in aspartate aminotransferase and alanine aminotransferase, and tiredness [60].

Moreover, Regorafenib, a kinase inhibitor that targets VEGFR, RAF, and PDGFR, has an even heavier toxicity profile, including pain, severe hand-foot skin responses, diarrhea, and all types of cytopenia, with up to 82% of patients reporting serious toxicities [64]. These toxicities are most likely the result of off-target effects on normal endothelium and epithelial cells, emphasizing the difficulty of balancing effectiveness and safety in kinase inhibition. The high frequency of serious adverse events associated with TKIs demands continuous surveillance, personalized dosage adjustments, and proactive management techniques to reduce toxicity while preserving therapeutic efficacy.

Selecting patients who are more likely to respond is necessary to improve response rates and spare patients from undergoing potentially treatment they are less likely to respond to [91]. While none of sHGFR, sVEGFR2, HGF, and VEGFA showed a statistically significant association with outcomes or treatment response in ES, Italiano et al. suggested that fluorodeoxyglucose (FDG)-positron emission tomography (PET) may help predict a favorable response to cabozantinib [60]. Researchers must systematically determine the validity of various potential biomarkers suggested by preclinical studies. Patients with biomarkers indicative of response to multiple TKIs might benefit from being administered several of these TKIs, either sequentially or simultaneously. This approach may perhaps only be implemented in the distant future, as studies assessing the reliability of biomarkers and the efficacy of TKIs are scarce, with a relatively low number of ES patients stemming from the rarity of this histology of bone tumors. Cooperation between university hospitals, specialized centers and other institutions is needed to address this problem.

TKIs are usually initiated after patients have progressed following several prior lines of therapy. Patients may not be able to tolerate TKIs as well as if they were introduced earlier in the course of the disease. We suggest assessing TKI therapy as a first line therapy in the treatment of ES, as was proven to be beneficial for mutant-EGFR-bearing non-small-cell lung cancer patients [92]. Another improvement that could be made in regard to the safety and toxicity assessments would be to include quality of life assessments in trials, instead of merely branding the toxicity profile as acceptable. Doing so would enable researchers to take into account the perspective of patients and provide additional insights about the toxicity of TKIs [91].

Frequent mechanisms of resistance to TKIs include but are not limited to the amplification of the targeted RTK, mutations in the gene coding for RTKs preventing TKI binding, and reduced TKI uptake by malignant cells. These mechanisms of resistance to TKI therapy will almost always occur, and strategies to counter them are necessary [93]. Possible ways to tackle this issue include the development of new generation TKIs capable of binding RTKs resistant to inhibitors and to use TKIs in combined therapies with other TKIs or with other modalities of treatment [94]. Those measures may contribute to extend survival and enhance patient outcomes.

Conclusion

This study sheds light on the crucial role of RTKs in ES, clarifying their impact on carcinogenesis and metastasis. Certain TKIs have shown encouraging results in the treatment of ES, highlighting the possibility for tailored therapy. As research advances, the identification of more biomarkers and the investigation of combinational therapy regimens may improve therapy success. This comprehensive study lays the groundwork for expanding precision medicine techniques in ES care, encouraging a more nuanced understanding of the molecular underpinnings of this aggressive bone cancer, and opening the path for new therapeutic regimens.

Data availability

Data is Available upon reasonable request from the corresponding author.

Abbreviations

ES:

Ewing’s Sarcoma

EWSR1:

Ewing sarcoma breakpoint region

FLI:

Friend leukemia integration

EFTs:

Ewing’s Family Tumors

TLS/FUS:

Translocated in liposarcoma/fused in sarcoma

ETS:

E26 transformation-specific

ERG:

Erythroblast transformation-specific-related gene

ETV4:

E twenty-six variant transcription factor 4

FEV:

Fetal hematopoiesis regulator

RTK:

Tyrosine kinase receptors

TKI:

Tyrosine kinase inhibitors

MAPK:

Mitogen activated protein kinase

PI3K:

Phosphatidylinositol 3-kinase

Akt:

Protein kinase B

mTOR:

Mammalian target of rapamycin

Ras:

Rat sarcoma

sVEGFR2:

Soluble VEGFR2

HGF:

Hepatocyte growth factor

sHGFR:

Soluble HGFR

PNET:

Ewing’s sarcoma/primitive neuroectodermal tumors

GTPase:

Guanosine triphosphatase

IGF1R:

Insulin-like growth factor 1 receptor

IGF1:

Insulin-like growth factor 1

IGFBP3:

Insulin-like growth factor binding protein 3

OS:

Overall survival

PFS:

Progression-free survival

Ki67:

Kiel 67

ABCA6:

ATP binding cassette subfamily A member 6

EHD1:

Epidermal growth factor receptor substrate 15 (EPS15) Homology Domain containing

EPS15:

Epidermal growth factor receptor substrate 15

VEGFR:

Vascular endothelial growth factor receptor

VEGF:

Vascular endothelial growth factor

EGFR:

Epidermal growth factor receptor

HER:

Human epidermal growth factor receptor

IHC:

Immunohistochemistry

LSAB:

Labeled streptavidin-biotin complex

KIT:

Stem-cell factor receptor

SCF:

Stem-cell factor

PDGFR:

Platelet-derived growth factor receptor

PDGFA:

Platelet-derived growth factor A

HGFR:

Hepatocyte growth factor receptor

c-MET:

Mesenchymal-epithelial transition factor

Ret:

Rearranged during transfection

ORR:

Overall response rate

AE:

Adverse event

FGFR1:

Fibroblast growth factor receptor 1

Flt − 3:

Feline McDonough Sarcoma-like trosine kinase 3

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Acknowledgements

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Authors and Affiliations

  1. Hematology-Oncology Department, Hotel Dieu de France, Beirut, Lebanon

    Ahmad Assi, Mohamad Farhat, Rami Mohanna, Maria Catherine Rita Hachem, Ziad Zalaquett, Sami Abi Farraj & Hampig-Raphaël Kourie

  2. Orthopedics Department, Hotel Dieu de France, Beirut, Lebanon

    Marven Aoun, Mohammad Daher & Amer Sebaaly

  3. Orthopedics Department, Brown University, Providence, RI, USA

    Mohammad Daher

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Contributions

A.A., M.F., R.M., M.H., and Z.Z. wrote the original draft, M.A., S.A.F., and M.D. were responsible for data curation. A.S. and H.K. reviewed and edited the manuscript. All authors approved the final draft.

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Assi, A., Farhat, M., Mohanna, R. et al. Tyrosine kinase inhibitors in Ewing’s sarcoma: a systematic review. BMC Cancer 25, 735 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14130-y

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14130-y

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BMC Cancer

ISSN: 1471-2407

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