The Role of Tyrosine Kinases as a Critical Prognostic Parameter and Its Targeted Therapies in Ewing Sarcoma.

Wook Jin

doi:10.3389/fcell.2020.00613

Abstract

Ewing sarcoma (ES) is a rare, highly aggressive, bone, or soft tissue-associated tumor. Although this sarcoma often responds well to initial chemotherapy, 40% of the patients develop a lethal recurrence of the disease, with death recorded in 75–80% of patients with metastatic ES within 5 years, despite receiving high-dose chemotherapy. ES is genetically well-characterized, as indicated by the EWS-FLI1 fusion protein encoded as a result of chromosomal translocation in 80–90% of patients with ES, as well as in ES-related cancer cell lines. Recently, tyrosine kinases have been identified in the pathogenesis of ES. These tyrosine kinases, acting as oncoproteins, are associated with the clinical pathogenesis, metastasis, acquisition of self-renewal traits, and chemoresistance of ES, through the activation of various intracellular signaling pathways. This review describes the recent progress related to cellular and molecular functional roles of tyrosine kinases in the progression of ES.

Highlights

The tyrosine kinase family, including both receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases, triggers a cascade of downstream signaling pathways that control the complex biological process of cells, including proliferation, cellular organization, and differentiation
Recent studies have demonstrated that activation of several tyrosine kinases, identified as potential therapeutic targets, enhances tumor growth and metastasis, developing chemoresistance in Ewing sarcoma (ES) cells through the activation of various intracellular downstream signaling pathways
Clinical observations and preclinical trials have reported that monotherapy, as well as combination therapy with such inhibitors, can efficiently combat ES, further investigations with novel multifaceted therapeutic strategies are required

Summary

Introduction

The tyrosine kinase family, including both receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases, triggers a cascade of downstream signaling pathways that control the complex biological process of cells, including proliferation, cellular organization, and differentiation. Both IGF-1R inhibitor and mTOR inhibitor treatment significantly reduced the tumor growth in ES xenografts through inhibition of IGF-1R/PI3K/AKT/mTOR, FIGURE 1 | Induced activation of IGF-1R facilitates the survival, metastasis, and chemoresistance in Ewing sarcoma (ES) by activating downstream signaling pathways.

Results

Conclusion