A research team led by Bruna Almeida dos Santos and Caroline Brunetto de Farias announced on Aug. 10 that delayed growth of SK-ES-1 Ewing sarcoma tumor xenografts is associated with reduced Trk and IGF1R pathway markers, according to a paper published in Volume 17 of Oncotarget.
The study, conducted at the Federal University of Rio Grande do Sul and the National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology, investigated whether targeting tropomyosin receptor kinase (Trk) and related signaling pathways could interfere with Ewing sarcoma growth. The researchers used K252a, a non-specific multi-kinase inhibitor with activity against Trk receptors, to treat human SK-ES-1 Ewing sarcoma cells grown as tumors in immunodeficient mice. Mice received daily intraperitoneal injections of K252a or vehicle for 18 days after tumors reached approximately 80–100 mm³.
K252a treatment significantly slowed tumor growth between days 9 and 15; however, by day 18, tumor sizes in treated mice were similar to those in the control group. No significant differences were observed in body weight or measured serum biochemical markers between groups. Tumor tissue analysis showed significantly reduced total and phosphorylated levels of TrkA, TrkB, PI3K, as well as total and phosphorylated insulin-like growth factor 1 receptor (IGF1R) levels in treated tumors; TrkC levels remained unchanged.
The authors cautioned that because K252a inhibits multiple protein kinases rather than selectively targeting Trk receptors, it is not possible to attribute the delayed tumor growth solely to one pathway. They wrote, "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."
Further experiments found that combining K252a with a selective IGF1R inhibitor produced a greater reduction in cell viability than either compound alone in cultured SK-ES-1 cells. The researchers also examined gene-expression datasets from patients with Ewing sarcoma: higher NTRK2 expression was linked to shorter overall survival in one cohort while higher NTRK1 expression was linked to longer survival in another; NTRK3 associations varied between cohorts.
The findings suggest that K252a can temporarily slow the growth of SK-ES-1 Ewing sarcoma xenografts while reducing markers associated with key signaling pathways. However, limitations include use of a single cell line-derived model and broad kinase activity of K252a; future studies are needed using additional models and more selective inhibitors.
