Abstract
Rhabdoid tumors (RT) are among the most aggressive tumors in early childhood. Overall survival remains poor, and treatment only effectively occurs at the cost of high toxicity and late adverse effects. It has been reported that the neurokinin-1 receptor/ substance P complex plays an important role in cancer and proved to be a promising target. However, its role in RT has not yet been described. This study aims to determine whether the neurokinin-1 receptor is expressed in RT and whether neurokinin-1 receptor (NK1R) antagonists can serve as a novel therapeutic approach in treating RTs. By in silico analysis using the cBio Cancer Genomics Portal we found that RTs highly express neurokinin-1 receptor. We confirmed these results by RT-PCR in both tumor cell lines and in human tissue samples of various affected organs. We demonstrated a growth inhibitory and apoptotic effect of aprepitant in viability assays and flow cytometry. Furthermore, this effect proved to remain when used in combination with the cytostatic cisplatin. Western blot analysis showed an upregulation of apoptotic signaling pathways in rhabdoid tumors when treated with aprepitant. Overall, our findings suggest that NK1R may be a promising target for the treatment of RT in combination with other anti-cancer therapies and can be targeted with the NK1R antagonist aprepitant.
Highlights
Rhabdoid tumors (RT) are rare and highly aggressive tumors primarily affecting infants and young children [1,2,3]
It has been previously demonstrated that the neurokinin-1 receptor (NK1R)/SP complex serves as a target in a large variety of cancers, including pediatric malignancies such as neuroblastoma and hepatoblastoma [19,20,31,32,33]
Due to the lack of an effective conventional therapy regimen and the high toxicity of chemDue to the lack of an effective conventional therapy regimen and the high toxicity of otherapy, patients suffering from rhabdoid tumors have poor overall survival rates [11,12]
Summary
Rhabdoid tumors (RT) are rare and highly aggressive tumors primarily affecting infants and young children [1,2,3]. They have been reported to be located in several organ compartments, such as the central nervous system (CNS) (referred to as atypical teratoid/rhabdoid tumor [AT/RT]), kidneys (RT of the kidney [RTK]), the liver, and soft tissue (extrarenal RT, malignant RT [MRT]) [1,3,4,5,6,7]. One of the genetic hallmarks of RTs is a loss-of-function mutation of the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), named integrase interactor. The lack of standard effective therapy, considerable concern about the toxicity of the chemotherapeutics, and late adverse effects require an improvement in the treatment of RT [1,2,9,12,13,14]
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