Efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell lines

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....

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Bibliographic Details
Published in:Scientific reports 2021-03, Vol.11 (1), p.6685-6685, Article 6685
Main Authors: Taniguchi, Keisuke, Konishi, Hiroaki, Yoshinaga, Akiko, Tsugane, Momomi, Takahashi, Hiroyuki, Nishisaka, Fukiko, Shishido, Yoshiyuki, Asai, Akira
Format: Article
Language:English
Subjects:
631/154/436
631/67/1059/602
Antitumor activity
BCR-ABL protein
Body weight
Body weight loss
Cell survival
Epidermal growth factor
Epidermal growth factor receptors
Fusion protein
Humanities and Social Sciences
Imatinib
Kinases
Lymphoma
Metastases
multidisciplinary
Protein-tyrosine kinase
Science
Science (multidisciplinary)
Stat3 protein
Synergistic effect
Transcription
Tumor cell lines
Xenografts
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Summary: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 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 future clinical settings.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-86021-8