The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents.
- Spriano F Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Chung EYL Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Gaudio E Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Tarantelli C Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Cascione L Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Napoli S Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Jessen K Oncternal Therapeutics, San Diego, California.
- Carrassa L Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
- Priebe V Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Sartori G Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Graham G Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
- Selvanathan SP Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
- Cavalli A Università della Svizzera italiana, Institute of Biomedical Research, Bellinzona, Switzerland.
- Rinaldi A Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Kwee I Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Testoni M Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Genini D Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
- Ye BH Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, New York.
- Zucca E Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Stathis A Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Lannutti B Oncternal Therapeutics, San Diego, California.
- Toretsky JA Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
- Bertoni F Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland. frbertoni@mac.com.
- 2019-06-12
Published in:
- Clinical cancer research : an official journal of the American Association for Cancer Research. - 2019
Animals
Antineoplastic Agents
Apoptosis
Biomarkers, Tumor
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Drug Synergism
Gene Expression Profiling
Humans
Immunohistochemistry
Indoles
Lymphoma
Mice
Prognosis
Protein Binding
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-ets
Transcriptome
Xenograft Model Antitumor Assays
English
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.
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/1078-0432.CCR-18-2718
- PMID 31182435
- Persistent URL
- https://folia.unifr.ch/global/documents/210237
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