Filippo Spriano 1 , Elaine Yee Lin Chung 1 , Eugenio Gaudio 1 , Chiara Tarantelli 1 , Luciano Cascione 1,2 , Sara Napoli 1 , Katti Jessen 3 , Laura Carrassa 4 , Valdemar Priebe 1 , Giulio Sartori 1 , Garrett Graham 5 , Saravana P Selvanathan 5 , Andrea Cavalli 6 , Andrea Rinaldi 1 , Ivo Kwee 1,2,7 , Monica Testoni 1 , Davide Genini 1 , B Hilda Ye 8 , Emanuele Zucca 9 , Anastasios Stathis 9 , Brian Lannutti 3 , Jeffrey A Toretsky 5 , Francesco Bertoni 10 Show Affiliations »
Abstract
PURPOSE: Transcription factors are commonly deregulated in cancer, and they have been widely considered as difficult to target due to their nonenzymatic mechanism of action. Altered expression levels of members of the ETS-transcription factors are often observed in many different tumors, including lymphomas. Here, we characterized two small molecules, YK-4-279 and its clinical derivative, TK-216, targeting ETS factors via blocking the protein-protein interaction with RNA helicases, for their antilymphoma activity. EXPERIMENTAL DESIGN: The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination; validation experiments on in vivo models; and transcriptome and coimmunoprecipitation experiments. RESULTS: YK-4-279 and TK-216 demonstrated an antitumor activity across several lymphoma cell lines, which we validated in vivo. We observed synergistic activity when YK-4-279 and TK-216 were combined with the BCL2 inhibitor venetoclax and with the immunomodulatory drug lenalidomide. YK-4-279 and TK-216 interfere with protein interactions of ETS family members SPIB, in activated B-cell-like type diffuse large B-cell lymphomas, and SPI1, in germinal center B-cell-type diffuse large B-cell lymphomas. CONCLUSIONS: The ETS inhibitor YK-4-279 and its clinical derivative TK-216 represent a new class of agents with in vitro and in vivo antitumor activity in lymphomas. Although their detailed mechanism of action needs to be fully defined, in DLBCL they might act by targeting subtype-specific essential transcription factors. ©2019 American Association for Cancer Research.
PURPOSE: Transcription factors are commonly deregulated in cancer , and they have been widely considered as difficult to target due to their nonenzymatic mechanism of action. Altered expression levels of members of the ETS-transcription factors are often observed in many different tumors , including lymphomas . Here, we characterized two small molecules, YK-4-279 and its clinical derivative, TK-216, targeting ETS factors via blocking the protein-protein interaction with RNA helicases, for their antilymphoma activity. EXPERIMENTAL DESIGN: The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination; validation experiments on in vivo models; and transcriptome and coimmunoprecipitation experiments. RESULTS: YK-4-279 and TK-216 demonstrated an antitumor activity across several lymphoma cell lines, which we validated in vivo. We observed synergistic activity when YK-4-279 and TK-216 were combined with the BCL2 inhibitor venetoclax and with the immunomodulatory drug lenalidomide . YK-4-279 and TK-216 interfere with protein interactions of ETS family members SPIB , in activated B-cell-like type diffuse large B-cell lymphomas , and SPI1 , in germinal center B-cell-type diffuse large B-cell lymphomas . CONCLUSIONS: The ETS inhibitor YK-4-279 and its clinical derivative TK-216 represent a new class of agents with in vitro and in vivo antitumor activity in lymphomas . Although their detailed mechanism of action needs to be fully defined, in DLBCL they might act by targeting subtype-specific essential transcription factors. ©2019 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
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Year: 2019
PMID： 31182435 DOI： 10.1158/1078-0432.CCR-18-2718
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531