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Small‐molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma
Author(s) -
Boro Aleksandar,
Prêtre Kathya,
Rechfeld Florian,
Thalhammer Verena,
Oesch Susanne,
Wachtel Marco,
Schäfer Beat W.,
Niggli Felix K.
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27472
Subject(s) - midostaurin , fli1 , cancer research , sarcoma , ewing's sarcoma , biology , gene expression , etoposide , doxorubicin , transcription factor , gene , genetics , medicine , pathology , chemotherapy , myeloid leukemia
Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well‐characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read‐out system, we screened a small‐molecule compound library enriched for FDA‐approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit‐list of nine well‐known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo . These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes.