Neurotensin receptor 1 is a new therapeutic target for human undifferentiated pleomorphic sarcoma growth

Abstract

Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G‐protein‐coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real‐time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5‐ to 7‐fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal‐regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.

Current research and management of undifferentiated pleomorphic sarcoma/myofibrosarcoma

“…Neurotensin receptor 1 (NTSR1) was a component of GPCR, and its knockdown significantly prevented the aggressive behavior of UPS cells. SR48692, an inhibitor of NTSR1, was found to synergistically coordinate with chemotherapeutic agents to prevent UPS cell proliferation by inactivating extracellular kinase ( Tokumoto et al, 2019 ). NTSR1 might be another target for UPS treatment.…”

Retroperitoneal undifferentiated pleomorphic sarcoma with total nephrectomy: a case report and literature review

“…Christina L. Roland found that cyclin D1, pEGFR, pIGF-1R, and PTEN deletion ( p < 0.001) and AXL overexpression ( p = 0.015) were associated with reduced disease-specific survival (DSS) ( 58 ). In addition, neurotensin receptor 1 (NTSR1) ( 59 ), anti-human tumor endothelin 1 (TEM-1) ( 60 ), and various other targeted therapeutic targets are under progressive research by related scholars and may become effective for the treatment of this disease in the future.…”

A Detailed Examination of Retroperitoneal Undifferentiated Pleomorphic Sarcoma: A Case Report and Review of the Existing Literature

“…Research into the cell signaling pathways and cell cycle regulation in UPS has paved the way for the use of phosphoinositide 3-kinase (PI3K) inhibitors, which, when combined with agents like doxorubicin, have significantly delayed tumor growth [87]. The exploration of other targets, such as Neurotensin Receptor 1 (NTSR1) and Fibroblast Growth Factor 23 (FGF23), continues to provide new insights into potential therapeutic strategies that could impede the aggressive behavior and proliferation of UPS cells [29,88].…”