Antitumour effects and mechanisms of action of the panHER inhibitor, dacomitinib, alone and in combination with the STAT3 inhibitor, S3I-201, in human sarcoma cell lines.

Abstract

The 5-year survival rate for metastatic sarcoma is 16%. Although the phosphorylated human epidermal growth factor receptor (pEGFR/HER1) has been shown to be an independent predictor of overall survival in patients with sarcoma, we have previously demonstrated that sarcoma cell lines exhibit resistance, despite gefitinib blocking p-EGFR and signal transducers in EGFR downstream pathways. Gefitinib failed to decrease the ratio of phosphorylated (p-)signal transducer and activator of transcription (STAT3)/p-STAT1, suggesting that relative STAT3 abundance and activation may be involved in drug resistance. In this study, we used the panHER inhibitor, dacomitinib, to further block HER2-dependent activation, applying multiple methods, such as proliferation assay, clonogenic survival assay, anti-anoikis assay and western blot analysis. Although dacomitinib inhibited EGFR, HER2, AKT and Erk activation more effectively than gefitinib, it still only exerted minimal anti-proliferative effects on sarcoma cell lines due to the STAT3 escape pathway. However, the addition of the STAT3 inhibitor, S3I-201, to dacomitinib achieved a significant enhancement in growth inhibition, by perturbing p-STAT3/p-STAT1. Using a panel of sarcoma cell lines with different histological types, we identified that the addition of the STAT3 inhibitor enhanced the growth inhibitory effects of the panHER inhibitor, dacomitinib, on sarcoma cells. Our findings may have clinical implications on overcoming the resistance caused by the STAT3 escape pathway and optimising EGFR/panHER-targeted therapy in sarcoma.

• Authors: Xiaochun Wang, David Goldstein, Philip J Crowe, Jia-Lin Yang
• Journal: International journal of oncology (Int J Oncol) Vol. 52 Issue 6 Pg. 2143-2154 (Jun 2018) ISSN: 1791-2423 [Electronic] Greece
• PMID: 29620166 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Aminosalicylic Acids
• Benzenesulfonates
• NSC 74859
• Quinazolinones
• STAT3 Transcription Factor
• STAT3 protein, human
• dacomitinib
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Aminosalicylic Acids (pharmacology)
• Benzenesulfonates (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Screening Assays, Antitumor
• Drug Synergism
• ErbB Receptors (metabolism)
• Humans
• Phosphorylation (drug effects)
• Quinazolinones (pharmacology)
• Receptor, ErbB-2 (metabolism)
• STAT3 Transcription Factor (metabolism)
• Sarcoma (drug therapy, metabolism)