Development of an Ewing sarcoma cell line with resistance to EWSFLI1 inhibitor YK4279.
Mol Med Rep
; 21(3): 1667-1675, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-32016454
ABSTRACT
Despite Ewing sarcoma (ES) being the second most common pediatric malignancy of bone and soft tissue, few novel therapeutic approaches have been introduced over the past few decades. ES contains a pathognomonic chromosomal translocation that leads to a fusion protein between EWSR1 and an ets family member, most often FLI1. EWSFLI1 is the most common type of fusion protein and is a wellvetted therapeutic target. A small molecule inhibitor of EWSFLI1, YK4279 (YK) was developed with the intention to serve as a targeted therapy option for patients with ES. The present study investigated resistance mechanisms by developing an ES cell line specifically resistant to YK. The ES cell line A4573 was treated with YK to create resistant cells by long term continuous exposure. The results revealed that resistance in A4573 was robust and sustainable, with a >27fold increase in IC50 lasting up to 16 weeks in the absence of the compound. Resistant ES cells were still sensitive to standard of care drugs, including doxorubicin, vincristine and etoposide, which may be valuable in future combination treatments in the clinic. Resistant ES cells revealed an increased expression of CD99. RNA sequencing and qPCR validation of resistant ES cells confirmed an increased expression of ANO1, BRSK2 and IGSF21, and a reduced expression of COL24A1, PRSS23 and RAB38 genes. A functional association between these genes and mechanism of resistance remains to be investigated. The present study created a cell line to investigate YK resistance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Ewing
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Proteínas de Fusão Oncogênica
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Resistencia a Medicamentos Antineoplásicos
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Proteína EWS de Ligação a RNA
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Inibidores de Proteínas Quinases
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Proteína Proto-Oncogênica c-fli-1
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Indóis
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Mol Med Rep
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos