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 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.

EML4-ALK Variant 3 Promotes Mitotic Errors and Spindle Assembly Checkpoint Deficiency Leading to Increased Microtubule Poison Sensitivity

“…Previous investigations have revealed synergy of ALK inhibitors with other classes of drug in cells expressing EML4-ALK fusions. For example, dasatinib (an ABL and SRC kinase inhibitor) produced a synergistic response with crizotinib in both H3122 and H2228 cells (37), whereas a STAT3 inhibitor, YHO-1701, exhibited synergy with alectinib, crizotinib, and ceritinib in H2228 cells (38). Other studies have found ceritinib and paclitaxel to be highly synergistic in the treatment of lung cancer cells with activation of the FAK even if they do not express EML4-ALK fusions (39).…”

Review of Personalized Medicine and Pharmacogenomics of Anti-Cancer Compounds and Natural Products

“…In nude mice, alectimib at a dose of 6 mg/kg significantly inhibited the growth of NCI-H2228 and KARPAS -299 cell transplantation tumors. In terms of the ability to overcome mutations, 100nM alectimib inhibited the phosphorylation of ALK in BaF3/EML4-ALK -L1196M cells [93,94]. 3) Brigatinib Brigatinib is a dual target inhibitor of ALK and epidermal growth factor receptor (EGFR).…”