"Significant associations between expression of NTRK genes and patient OS were found, indicating that NTRK genes should be further evaluated as biomarkers for prognosis in patients with ES."
BUFFALO, NY – August 10, 2026 – A new research paper was published in Volume 17 of Oncotarget on August 7, 2026, titled " Delayed growth of SK-ES-1 Ewing sarcoma tumor xenografts is associated with reduced Trk and IGF1R pathway markers ."
The study was led by first author Bruna Almeida dos Santos and corresponding author Caroline Brunetto de Farias, primarily affiliated with the Federal University of Rio Grande do Sul and the National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology (INCT BioOncoPed) , with de Farias also affiliated with the Children's Cancer Institute (ICI) in Brazil . The research team investigated whether targeting tropomyosin receptor kinase (Trk) and related signaling pathways could interfere with Ewing sarcoma growth.
Ewing sarcoma is an aggressive cancer that primarily affects children and adolescents and can arise in bone or soft tissue. Although modern multimodal treatments have substantially improved outcomes for patients with localized disease, the prognosis remains considerably poorer for metastatic or relapsed Ewing sarcoma. This has driven efforts to identify molecular pathways that could provide additional therapeutic targets.
One potential target involves the Trk family of receptor tyrosine kinases. TrkA, TrkB, and TrkC are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively, and regulate intracellular signaling pathways involved in cell survival, differentiation, and growth. Previous work from the research group showed that TrkA and TrkB are expressed in Ewing sarcoma and that blocking these receptors can reduce tumor-cell proliferation.
In the new study, the researchers examined the effects of K252a, a non-specific multi-kinase inhibitor with activity against Trk receptors, using human SK-ES-1 Ewing sarcoma cells grown as tumors in immunodeficient mice. After tumors reached approximately 80–100 mm³, mice received daily intraperitoneal injections of K252a at 0.5 mg/kg or vehicle for 18 days.
K252a treatment significantly slowed tumor growth during part of the treatment period, with the effect particularly apparent between days 9 and 15. However, the response was temporary: by day 18, tumor sizes in treated mice had returned to levels comparable to those in the control group. The researchers observed no significant differences in body weight or the measured serum biochemical markers between the groups.
Analysis of tumor tissue provided additional evidence that K252a affected several signaling pathways. Treated tumors showed significantly reduced total and phosphorylated levels of TrkA and TrkB, as well as phosphoinositide 3-kinase (PI3K). Total and phosphorylated insulin-like growth factor 1 receptor (IGF1R) levels were also reduced, whereas TrkC levels remained unchanged.
Because K252a inhibits multiple protein kinases rather than selectively targeting Trk receptors, the researchers caution against attributing the delayed tumor growth to any single pathway. The observed reductions in TrkA, TrkB, PI3K, and IGF1R signaling may contribute to the antitumor effect, but other kinase targets of K252a could also be involved.
"In summary, we report evidence suggesting that treatment with the multi-kinase inhibitor K252a is associated with inhibition of Trks, PI3K, and IGF1R and can transiently delay ES tumor growth."
The researchers also explored whether simultaneously interfering with Trk-related and IGF1R signaling could produce a stronger effect. In cultured SK-ES-1 cells, K252a and the selective IGF1R inhibitor NVP-ADW742 individually produced relatively small reductions in cell viability at the tested concentrations. Combining the two compounds produced a significantly greater reduction in viability than either treatment alone, supporting further investigation of therapeutic strategies targeting interacting signaling pathways.
Finally, the researchers examined whether expression of NTRK genes was associated with overall survival in patients with Ewing sarcoma using two independent gene-expression datasets. Higher NTRK2 expression was associated with shorter overall survival in the Children's Oncology Group cohort, whereas higher NTRK1 expression was associated with longer survival in the EuroEwing cohort. NTRK3 showed contrasting associations between the two patient populations. These associations remained statistically significant after correction for multiple comparisons, but the authors emphasize that the cohorts were relatively small and that these findings should be considered exploratory and hypothesis-generating until validated in larger, independent patient populations.
Overall, the findings suggest that K252a can temporarily slow the growth of SK-ES-1 Ewing sarcoma xenografts while reducing markers associated with Trk, PI3K, and IGF1R signaling. However, the use of a single cell line-derived xenograft model and the broad kinase activity of K252a limit how far the results can currently be generalized. The researchers propose that future studies should test additional Ewing sarcoma models and investigate more selective inhibitors to clarify the individual contributions of these signaling pathways.
DOI: https://doi.org/10.18632/oncotarget.28911
