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

  • Authors:
    • Xiaochun Wang
    • David Goldstein
    • Philip J. Crowe
    • Jia-Lin Yang
  • View Affiliations

  • Published online on: March 27, 2018     https://doi.org/10.3892/ijo.2018.4337
  • Pages: 2143-2154
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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.
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June-2018
Volume 52 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Wang X, Goldstein D, Crowe PJ and Yang J: 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. Int J Oncol 52: 2143-2154, 2018
APA
Wang, X., Goldstein, D., Crowe, P.J., & Yang, J. (2018). 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. International Journal of Oncology, 52, 2143-2154. https://doi.org/10.3892/ijo.2018.4337
MLA
Wang, X., Goldstein, D., Crowe, P. J., Yang, J."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". International Journal of Oncology 52.6 (2018): 2143-2154.
Chicago
Wang, X., Goldstein, D., Crowe, P. J., Yang, J."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". International Journal of Oncology 52, no. 6 (2018): 2143-2154. https://doi.org/10.3892/ijo.2018.4337