TY - JOUR
T1 - The ETS inhibitors YK-4-279 and TK-216 are novel antilymphoma agents
AU - Spriano, Filippo
AU - Chung, Elaine Yee Lin
AU - Gaudio, Eugenio
AU - Tarantelli, Chiara
AU - Cascione, Luciano
AU - Napoli, Sara
AU - Jessen, Katti
AU - Carrassa, Laura
AU - Priebe, Valdemar
AU - Sartori, Giulio
AU - Graham, Garrett
AU - Selvanathan, Saravana P.
AU - Cavalli, Andrea
AU - Rinaldi, Andrea
AU - Kwee, Ivo
AU - Testoni, Monica
AU - Genini, Davide
AU - Ye, B. Hilda
AU - Zucca, Emanuele
AU - Stathis, Anastasios
AU - Lannutti, Brian
AU - Toretsky, Jeffrey A.
AU - Bertoni, Francesco
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/8/15
Y1 - 2019/8/15
N2 - Purpose: Transcription factors are commonly deregulated Results: YK-4-279 and TK-216 demonstrated an antitumor in cancer, and they have been widely considered as difficult activity across several lymphoma cell lines, which we validated to target due to their nonenzymatic mechanism of action. in vivo. We observed synergistic activity when YK-4-279 and Altered expression levels of members of the ETS-TK-216 were combined with the BCL2 inhibitor venetoclax transcription factors are often observed in many different and with the immunomodulatory drug lenalidomide. tumors, including lymphomas. Here, we characterized YK-4-279 and TK-216 interfere with protein interactions of two small molecules, YK-4-279 and its clinical derivative, ETS family members SPIB, in activated B-cell–like type TK-216, targeting ETS factors via blocking the protein–diffuse large B-cell lymphomas, and SPI1, in germinal center protein interaction with RNA helicases, for their antilym-B-cell–type diffuse large B-cell lymphomas. phoma activity. Conclusions: The ETS inhibitor YK-4-279 and its clinical Experimental Design: The study included preclinical in vitro derivative TK-216 represent a new class of agents with in vitro activity screening on a large panel of cell lines, both as and in vivo antitumor activity in lymphomas. Although their single agent and in combination; validation experiments on detailed mechanism of action needs to be fully defined, in in vivo models; and transcriptome and coimmunoprecipita-DLBCL they might act by targeting subtype-specific essential tion experiments. transcription factors.
AB - Purpose: Transcription factors are commonly deregulated Results: YK-4-279 and TK-216 demonstrated an antitumor in cancer, and they have been widely considered as difficult activity across several lymphoma cell lines, which we validated to target due to their nonenzymatic mechanism of action. in vivo. We observed synergistic activity when YK-4-279 and Altered expression levels of members of the ETS-TK-216 were combined with the BCL2 inhibitor venetoclax transcription factors are often observed in many different and with the immunomodulatory drug lenalidomide. tumors, including lymphomas. Here, we characterized YK-4-279 and TK-216 interfere with protein interactions of two small molecules, YK-4-279 and its clinical derivative, ETS family members SPIB, in activated B-cell–like type TK-216, targeting ETS factors via blocking the protein–diffuse large B-cell lymphomas, and SPI1, in germinal center protein interaction with RNA helicases, for their antilym-B-cell–type diffuse large B-cell lymphomas. phoma activity. Conclusions: The ETS inhibitor YK-4-279 and its clinical Experimental Design: The study included preclinical in vitro derivative TK-216 represent a new class of agents with in vitro activity screening on a large panel of cell lines, both as and in vivo antitumor activity in lymphomas. Although their single agent and in combination; validation experiments on detailed mechanism of action needs to be fully defined, in in vivo models; and transcriptome and coimmunoprecipita-DLBCL they might act by targeting subtype-specific essential tion experiments. transcription factors.
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U2 - 10.1158/1078-0432.CCR-18-2718
DO - 10.1158/1078-0432.CCR-18-2718
M3 - Article
C2 - 31182435
AN - SCOPUS:85070874285
SN - 1078-0432
VL - 25
SP - 5167
EP - 5176
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -