Efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell lines
| Autor: | Keisuke Taniguchi, Hiroaki Konishi, Hiroyuki Takahashi, Fukiko Nishisaka, Momomi Tsugane, Yoshiyuki Shishido, Akiko Yoshinaga, Akira Asai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
STAT3 Transcription Factor
Alectinib Science Antineoplastic Agents Article Mice Targeted therapies Cell Line Tumor hemic and lymphatic diseases Biomarkers Tumor medicine Animals Humans Anaplastic lymphoma kinase Osimertinib Molecular Targeted Therapy Epidermal growth factor receptor Protein Kinase Inhibitors Cell Proliferation Pharmacology Multidisciplinary Dose-Response Relationship Drug Ceritinib biology Crizotinib Chemistry Drug Synergism Dasatinib Disease Models Animal Quinolines Cancer research biology.protein Medicine Combination drug medicine.drug |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Signal transducer and activator of transcription 3 (STAT3) plays a critical role in regulating cell growth, survival, and metastasis. STAT3 signaling is constitutively activated in various types of hematologic or solid malignancies. YHO-1701 has been developed as an orally available STAT3 inhibitor. Herein, YHO-1701 in combination with molecular-targeted agents was evaluated. Additive or synergistic effects were observed in a broad spectrum of “combination treatment + cell line” pairs. Of particular interest was the synergistic effect observed when YHO-1701 was combined with imatinib or dasatinib [breakpoint cluster region-abelson (BCR-ABL) inhibitors], osimertinib [epidermal growth factor receptor (EGFR) inhibitor], crizotinib, alectinib, or ceritinib [anaplastic lymphoma kinase (ALK) inhibitors]. The results further showed a close relationship between these synergistic effects and the cellular levels of the key molecules involved in the target pathways for YHO-1701 and each combination drug. The combination of YHO-1701 with alectinib resulted in a significantly greater antitumor activity without exhibiting body weight loss in an NCI-H2228 [echinoderm microtubule–associated protein-like 4 (EML4)-ALK fusion] xenograft mouse model. Our results strongly suggest that the logical strategy in combination with the novel STAT3 inhibitor YHO-1701 and other mechanistically different targeted agents could be a promising approach in the clinical setting. |
| Databáze: | OpenAIRE |
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