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

Abstract

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.

• Authors: Keisuke Taniguchi, Hiroaki Konishi, Akiko Yoshinaga, Momomi Tsugane, Hiroyuki Takahashi, Fukiko Nishisaka, Yoshiyuki Shishido, Akira Asai
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 6685 (03 23 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33758275 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Protein Kinase Inhibitors
• Quinolines
• STAT3 Transcription Factor
• STAT3 protein, human
• YHO-1701

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Biomarkers, Tumor
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Humans
• Mice
• Molecular Targeted Therapy
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Quinolines (administration & dosage, pharmacology)
• STAT3 Transcription Factor (antagonists & inhibitors)